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PAR T IV
BIOLOGICAL ACTIVITY & CHARACTERISATION DATA
Section I
Biological Testing
354 INTltol)UCTION
175
Celltul'Y lifter celltul'Y scielltists hq;1l1l to establish a system of
\dlO\\'ledge ilased upon nccurnte, purposeful ollsel'vntiou, logical inference,
i I II II g i 1111 t i vc hyf'o the, i s, 11110 i Ilgell i ous ex pe I' i 111 e n ts designed to esta bl ish
illuisputllble filet. llcfol'e the tilile of I'liul Eherlich, father of chemothe-
[,ilpy. lIu' tlH'l'llpClIlies Ii~c eir\{'llOllH ror 11llllllrill. ipcul for amoebic dysentry
alld 1lH'1'('UI'Y for syphilis ha\'e Iwen used, ,\lti1Ough diseases of protozoal
,,,,ei spi ",willie till 01' igi 11 It II ve becil 111 ade t" respond to synt het ic chemo
tilel'[lpcutic agents durillg tile first t\\'o decades of 19th century, systematic
ilnetcl'inl illfections could bc tl'cnted witil dl'ugs until comparatively later,
'I'i1e l11icloiliologist ond elinielll pCl'sonllel 1l1'<'1'looked the possibility thot
ll,c IlIlctcriostlltic compounds would illllil,it tllc rnpid reproduction of potho
gellie bnctel'in ulld ellnlile the Icucoe~·tcs IIlld otller defence lI,echanism
of tile I,ost to copc Ilitlt fel'.' stlltil' ill\'lId('I'S,
'I'el'lll ellclliotil<'rIlI'Y Ils('d to <I""'l'il>(' tile cure of fin infectious
<Iiseasc without injury to the host olld tile drug used, known as chemo
lIr<'r:rpcutic ngcnts, \':Iliell Ilave bel'n clll"ifiecl llccordillg to the disease
lind tile infections, such os Hntilrnctcriol. antiprotozoal, antiviral, anti
Ij(~oplustie lIgcnts.
This section describes tile methods lIsed for tile "in vitro" assessment
of Hntibllctcriul, Ilntituber-culnl'. onticHllcer nnd Illlti-IlIV agents, Antibacter
illl Sllhsl<lll('~s III'C clllssiricd liS disinfC'elHllts. i.e. compounds which ore
lIsed to clilllinntc 01' dcstroy infections [lnd should be capalrle of killing
176
II wide runge of bacteria, Ilntiseptics, I.e. on ontimicrobial agent used
fur dccontulIlinlitioli of body sllrf!)(~e by preventing or arresting microbial
growth. Chemotherapeutics can be eilher bacteriostatic or bactericidal
in action, Iheir main funclion is 10 prevenl the multiplication of infective
oq~anisms so flS to allow the body funclions to deal more effectively
\-vi til illrc'et ions.
Tlte determination of Ihe scn,itivity of bncteria to antibacterial
suiJstanee usunlly involves the exposure of the slandard suspension of
bllclcriu 10 the effect of particular concentralion of the substance. Two
general methods are in use. In the tube dilution technique serial dilutions
of sllbstancc ol·e [lre[lnred, the orgnnisllls lire lidded and minimum inhibitory
concentration (MIC) reud visually or spectrophotometrically after incubation.
In the agar diffusion method, also called the cylinder-cup method, or
IIgllr cur method, small open ended cylinders are placed on the surface
of pre-seeded ngHr pill tes or wells of porI icular size are lliIade in the
[,,",,-seeded agllr plates, filled witlt suspension of substance -to be tested
nnd tlte plates me incubated. The compound (substance) diffuses into
tlie medium producing a concentration gradient. Bacterial growth is sup
pressed within a circular zone, the diameter of Which is a function of
MIC of the substance. lIere we have used agar diffusion method in which
results (diameter of zone of inhibition of orgs.) are compared for different
suilstunces with stllndnrd Antibacterial known substance. Factors affec9ng
IIII' experiment nrc nalure of culture mediulll used for growth of bacteria,
DgC of bllctcriDI culture, pll of the culture medium, temperature of incubat
ion (01' {(l"O\ltlt of blleter-ill, etc.
177
TilE OHGANISMS BACTERIA
The hue tel' iu used were represen I n t i yes of pa thogenic bacteria
from gram +ve and gram -ve groups as well as rod-shaped and round
shaped bncterial groups, i.e. Escherichia coli, Salmonella paratyphi A and
Staphylococcus aureus.
Escherichia coli : Cells BI'e members of the Enterobacteriauae family,
found in intestilllli tl'oct of llIan nlld Ilnimnls, also in woter, milk and
soil. They are the normol illllObitonts or normal flora of the human body,
I'emnin for 0 life time without producing nny disease in normal condition
of henlth, bllt they can invode body tissue under certain conditions of
health, so they are also known as opportunists. Most frequently cause
the urinary tract infection e.g. cystitis.
The cells are gram -ve, short, plum rods, sometimes coccus-like
(coccobacillary shnpe), occurring singly, in pnirs, or in short chains. Cells
fire 0.5 u brood and to 3 .JI long, motile, nonsporing, nonencapsulated.
The cells nre nerobic to fncultAtive onael'otJic. require optimum temperature
37°C for growth, ferment lactose, produce indole, gives methyl red test
positive, vogesproskaur reaction negAtive, no growth in citrate medium.
Salmonella paratyphi A: The organisms are pathogenic, cause paratyphoid
diseose in humon beings. The organisms ore short, plump rods, gram -ve,
occurs singly, in pairs, occasionally in short chains .. Cells are 0.6 to
0.7 U ill bl'cndtll IIlid 2 to 3 u in lellgth, Illolilc, nOllsporing, IlOllcncapsulated.
178
Tile organisms arc aer'olJic to fneul tative anaerobic, require optimum temp
erlltlll'e 37°C for growth, Inctose nonferlllenter, xylose is not fermented.
These bacterill are pyogenic cocci, occurs in
irregular clustors, singly, III pairs, in sliort chains. Cells are 0.8 to 1.0 u
in size, grnm tve, non-motile. nonsporing. nonencapsulated. The organisms
IIl'e IICI'obi" to fll('ultlltiv(' ,ullicro/)i('. optilllulII temperature for growth,
37°C, produ('e golden yellow pigmented colonies on Nutrient agar and
potlilo mediulll.
Tire culture medium:
Nutrient ngar mediulll was used,
medium is llS follows
Peptone 1.0
NIICI 0,5
MCl! t cxtrllct 0,3
Distilled watcr 100
1"1 7,6
Agar 2,0
Chemical composition of the
g
g
g
cc
g
The ingredients \'I ere wcighed and dissolved in distilled water,
pH was adjusted to 7,6 and tilen agar powder was added to it, put in a
boiling water bath until all agar dissolved in it. Then the medium was
dispensed in 25 III I qUl!ntity in differcnt test tubes. The test tubes were
plugged by cotton-lVool and sterilized at 121.5°C, 15 pounds pressure per
squIIl'e in('h (p,s,i.) for 15 minutcs.
179
TESTING OF ANTlTUIIEHCULAH ACTIVITY OF COMPOUNDS
SYNTIIESISED IN PAHTS I TO III
INTHODUCTION
IV1 yc obacterial diseases are tlie most ancient of mankind being
known in orientnl nn<l ~lcdlterellnClln Civilizlltion as long as 4000 years
ago. They are most protected of nil infections whether treated or un-
trenlcd Ilnd rcqllir·cd longcst IIlcrnpy; J to 6 doys for haeterial pneumonia
vis 540 to 730 days or more for tuberculosis and leprosy.
AI thougll tuberculosis is a problem of rapidly diminishing proportion
in Western Europe and North America, it remains in the words of World
Health Organization (W.H.O.) report 355,356 "The most important, speeifie
nnd the communicable disease in the world" and ttley estimate three million
new eases each year add to trngieally maintained total of atleast twenty
357 million ellses with thrce million dClltlis alllllllllly
Besides common pulmonary tuberculosis of lungs there are many
oiller types of disease, 1l11lncly tuberculosis, laryngitis, enteritis, osteomy-
eli tits, meningitis and host of others including rapidly fatal known as
miliary tuberculosis. The infectious nature of tuberculosis and its method
358 359 of trllnsrnission have been studied by Fracastorious but Villemin was
able to transmit the disease from man to rabbits. Baumgarten had possibly
fir·st seen tlie blleilills in the infectcd lissues curly in 1878 and tile credit
360 for Ihe discovery of the enuse of tUbereulosis goes to Robert Koch who
isoluled I\lycotJllclcrium tuhcrculosis in 1882. Hum/ln pulmonary tuberculosis
is cBused predominenlly by ~co""clc("ium tuberculosis (Var 1I0minis)
180
IIl1d 10 a sllllIll extelll by ~1. !lavis, olso designllted as M. tuberculosis
Vllr Hovis.
Characteristic of tuherele bacilli
The tllilerele bflcilli Are slender strllight, or slightly curved rods
witll roulHled end orr,lInisril. They vllry ill widlh frolll 0.2 to 0.5 urn and
ill length from 1 to 4 urn. The b/leilli are acid-fast, non-mali Is and non-
spurogenous hllvillg no cllpsules. Tubel·"le bneilli from either cultures
or secretions may be stained by the Ziehl-Neelsen method. With this
stain, the bacilli ol'e seen as brilliant red rods against a deep sky blue
background. The tubercle bncillius takes 18 to 24 hours to reproduce
60 tililes as compnred to pneumococcus.
Although chcmotherapy of tuberculosis hns been prBctised in some
form or the other, for over two thousand years it has been Il clinical
I'elility for the last three decades only. For a long lime the therapy
has been based on despoeration rather thnn on scientific prospects of
success. Primitive treatment for tuberculosis such liS injections of tanin 361
or of ani mill charcoal 362. black 363
mud baths large daily consumption
of spellen 364 and massive gold solt injections 301 persistep for mony years,
all these were reported by l(och 360 as effective against guinea pig tuber-
eulosis. True ehemotherllpy of tuberculosis beglln from 1935 Ilnd consider-
uble progress 11115 been made thereafter. There nre mBny obstacles that
('onfl'Olil the "Ii"motilcrllpy of tuberculosis. Some of them are
181
i) Tubercle bucillus survives for !l number of years in a host without
inducing any provocation.
ii) It is a slow growing organism which does not elicit a sharp and
massive reaction from the host.
iii) Tuberculosis is [l communicllble diseHse lind has existed as a constant
stress 011 human survival.
iv) The diseose cnuses extensive tissue destruction nnd live virulent
bacilli get protcction in the cavities, dcbries and narcotic tissues,
where they remain immune to chemottlerapeutic attack.
It was, therefore, considered nf'cessllrY to evolve an ideal, more
effect ive and snfer chemotherapeutic drug treatment for the deadly in-
rcetiolls disease. Thc drug so evolved should be slow in producing the
resistance strain and reilltively free from llndesirllble side effects.
Tubercle bllcilli vllceine known os "Bllcillus Cal matte Guerin" or
. 31"5 BeG 1. 11IIS bcen devcloped. Evcn though to dute there is no conclusive
evidpnce that vaccination with Il.C.G. confers acquired resistance on human
" "" "d d b bl I ". r b f" 366 being but It IS consl ere pro 11 e t wt It IS a some ene It .
The search of substance to antagonise the respiratory stimulants
of M. tuberculosis by salicylic acid led to the discovery of P.A.S~67.
1I0wever, the latter docs not effect the respiration or antagonise salicylic
lIeid wlliell in fnct is not respiratory substrate in the mycobacterium.
The rut ionnlc pcrsuit of s(,f'c(~niIlK hilS SOIlI(' t imo buen ralthful 89 a result
or (!OIllIllOU pl'ucliec of blind sercclling' of cliemical Inlcrrnediates Jli8
182
MODEItN METIIODS OF TESTIN(; OF TUIIEItCULOSTATIC DRUGS
(1\) In vitro tests
Tile in vitro tcsts principnlly consist of seeding tubercle bacilli
into II synthetic culture medium. This consists of graded concentrations
of the substance to be tested, ranging from zero concentration for control
plll'poses to concentr'lltion approHching the toxic dose. The in vitro testing
11IIS got some lilllitutions but it is useful for specinl purpose such as for
structure Ilctivity stueiies, determination of antimyeobacter-ial spectrum,
checking up frequency of primnry resistnnce and effect of combination
therapy, comparison of intracellulllr with extrn cellular activity and guide
to clinical therapy, etc.
(U) In vivo test
In this tcst compounds to be tested ore applied to the animals
infected with dcsircd orgllnism, In this ellsc mice, guinea pigs, rabbits
or' monkeys inoculated with bovin tubercle bacilli, some of the infected
Hrlimals treated omlly as parenterally Ilt various dose levels with the
substllnce to be tested while others untrellted animals are maintained
as controls. A widely used technique following pathology of the disease
proceed by sllcrificing treated Alld untreated infected animals in which
tile inreetioll spread to voriolls orgnns. '1 he method of introducing the
tuherculosis infection Hl AnimAls is an importAnt fnctor in thc characteri
zntion of the diseHse process. Exhaustive reviews by different authors
hllve been published on this topic of tutwrculosis 36~-373
183
Tlie modern work could be considered to have started witll the
. fit· 374 ObSCI'VlItlOllS 0 1st Itich lind 1'01lis375
, tlieir findings that the large
closes of SuifonilEllTlicies produced a beneficinl
of experimental tuberculosis, wos confirmed
Cul.lll!:£ of M,Ycohncterium tuberculosis
effect on the development
376 by But tie and Parish
Sputum is the most common material suspected of containing tuber-
ele Imeilli. I\llIny ollicl· orgnnisms lire uSIIIIlly present and the plating
methods used in other bacteriological examinations are useless. Acid-
fust bucilli gl·ow ut very lTluch slower rate than other bacteria and are
overgrown on pili te cui tures. Isoln t ion method depend on homogenisation
of suspected specimen with a rengent thnt is less lethal for Mycobacterium
than other organisms.
Ilnrd rellgents are stl·ongly recommended for heavily contaminated
speeilllell. Exposurc timc is ('riti(,111 on the mycobacteria. Soft reagents
me pre f erred wllCre t here a re fewer orgll n isms, e.g. in freshly collected
s"utllm.
IInrd method
In this mcthod splltum ( 1 1111) is tr('nted with aqueous NaOIl (4%,
2 1111) sllliken rIle('hllJlicnlly for 15 to 30 rninlltes, in a screw (,/lped bottle,
neutrnlised with aqueous dipotllssium 11ydrogt'n orthophosphnte (11 %, 3 mil
lind centrifllged. The (jpposit cnn be used for the preparation of bacterial
SlIS[1<:>nSlOI1.
184
Soft method
In this method, sputum (2.4 ml) is treated with equal volume of
trisodium orthophosphate solution (a']. 23'\,) and left in contact at room
tempcmture or in a refrigerator for 18 hou,'s, diluted with distilled water
to reduce viscosity ond centrifuged.
Cui ture media
A wide variety of culture media is available, egg media is most
commonly used.
~I iddebrook 's 71110
ond 711 11 media is also useful. Kirchner's
liquid lIledia is useful for fluid specimen tlwt cannot be centrifuged or
when a lurge amount of material is to be cultured. The composi tion
C I I j.. I·· 377 o t well lure (nee Illm eHIl InCI'CliSe or dcerf'llse t Ie actIve concentratIOn .
378 Antibiotic media of ~Iitchison ct ul. is useful for contaminated speci-
mens.
Prepllrution of (,owenstcin - Jensen me<:lium
To the suit solution [1\112
1'04
(UI gm), ~lgS04.71120 (0.4 gm).
magnesiulll citrate (1.0 gm), L-llspergine (6.0 gm) and glycerol (20.0 m!)
ill 1000 III I of distilled water, stenmed for 2 hours and cooled]. starch
(00.0 gill) was added ond heoled at 56°C with slirring, the resulting paste
k('pt "' II wllter blllh Co,· 1 hour. A,rptiC'lIll,' hllncHed egg fluid (1600 mil
mixed Wl'1l with tile IIhove SlIit stlll'"h solution ond filtered through gauze.
TCl tlu' r(·...,ldtillf~ IIlixtlll'C', Illnlllcllitf' ~r(>[,1l (Ilq. l'bi 50 OJl) Hdded, stirred
185
und dislribuled in tulles, definile frH(~lion of test solution added, slopped
und inspissllted ot 85°C.
I . .•. . 379
noculatlOn and ItlcuuatlOn
ilaclerial suspension is prepared by inoeululing autoclaved phosphate
1)(lffer (pll 7.4; 2.0 ml) prepnred by dissolving anhydrous NaZllP0
4 (13.3 gm)
ond I( 1121'°
4 (3.5 gm)in distilled waleI' with loopful of culture and stirring
for' few minlltes. Elleil tube conlnining definite concentration of the
lcsl substnnccs is inoculated with obove suspension using a sterile loop
llnd incubutcd at 37°C for three to six wee~s.
Culturnl melilOds hove now largely superseded animal inoculations.
Hcltsons for ending the routine guinea pig test were given by Marks 379
There are three methods for sensitivity tests with mycobacteria.
The niJsolutc concentration method 380
In this method, carefully measured amount of the standardised
inocula plnced on medio containing graded concentration of test substance
rllnging from zero to higher eoncentrotions lind the lowest concentration
that inhibit all or nenrly all of the growth is recorded.
In Illis mell,od s('v('rtd dilulions of thc inoculum lire made and
186
used In ino"uluting control media contuining stllndard concentration of
lile test substances alld the lIumber of colonies growing on central and
clt'lIg eontailling tubes receiving the slime inoculation is studied.
. . 382 The resistullee ratIO method
, III lilis lIIetilod the millimulll inl,ii>itlH'Y eOllcentl'ution thut inhibit
test strllins ore dividcd by these which inhibit control strains to give
tile rcsisltllH'C rnlio. Hilt io !In" 2 lire considered us sensitive and 4
01' morc as resistant.
In the present work Lowellstein-Jensen medium has been used to
perf 01'111 sellsitivity tests,
III this sectioll porticulnrs of Ports I to III for their antitubercular
cd in tubles,
187
INTHOIlLJCTION TO MICHOIIIAL DISEASE 383
Those diseHse for which specific ""I'PS lire possible and for which
inllnllno pl'Ophylaxis is nvailable are caused primarily by infectious agents.
Tlwoughout the developing \\'orld, ncute infections, predominantly acute
dinrrheal illness ond acute rcspirlltory disense, are by far. the leading
('II uses of nlortlility, In Illore circuillserillcd areas of Asia, Africa and
South Amel'iell, protozoal disenscs (especially malaria) and helmenthic
infections (notably Schistosomillsis und olH"llocerciusis) continue to affect
millions of individunls nnd clluse hundreds of thousands of deaths annually.
A new infectious agent, the human immunodeficiency virus (HlY),
('InTently poses tile gl'eutest communicable disense challenging the twentieth
C'entury. Efforts to deal effectively with the disease created by this
retrovirus hnve eclipsed oUler infectious discnse problems at the present
time. IIIV, which was identified as the etiologic agent in the uniformly
flltlll ""quil'cd immunodeficiency syndrome (AIDS) has now infected over
H) million individllllis world wide, Although Ule prevalence of illY infect-
ion is greatest in central Africa, cases of AIIlS have now been identified
in over' two thirds of the nations of the world, and neither the rate nor
tile ultimate limits of its spread can be defined at the present time.
Current data indicate tilat 25 to 45 % of the individuals infected with
IIIV will develop AIDS witilin five to eight years of the initial infection.
Tile response of tile biomedical community to the IIiV challenge has been
swift and, in view of the complexicity of tile problem, well coordinated.
Tile clilliclil syndrome was recognised in In I, and the etiologic retrovirus
188
identified in 1983-8,1. Since tilen severol virul genes ilove been isolated,
SOllie of the gcncs hllve been cloned lilld sequenced, a number of the
gene products have been identified And the immune responses to both
the wllole virus nnet its products hllve been intensively studied.
1)0.spitc tlH~SC f'elllllrklibly (,lipid lIl'COJlIpiisillllcnts, neither B curative
tllf'rHl""'lic IIgent 1101' '''' effective vllccine hilS yet been developed. Azido
thymidine, an alltimetfibolite tllllt acts fiS A DNA-chain tel'minstor, does
effeetively delny diseAse progression III a Illrge subset of AIDS patients
Illit does not eliminate 111\'; progl'ession of the disease recurs following
cessation of therapy. Although a g;eat deal of effort is now directed
towal'd developing" more effective nntiretroviral agents, the incorporation
of tile IIIV proviral llNA into the genorne of the host cell greatly compli
cates uny attelnpt to eradicate the etiologic retrovirus. The efforts
to develop an effective vaccine are also impeded by a number of complex
I,,'oblerns. The extl"ll ordinllrily rllpid rntc of lIlutation of certain of the
Vi,'HI gencs, especially tilose coding for tile envelope glycoprotein, and
the known oncogenic effects of both IIIV and related retroviruses, make
tile development of an effective vllccine exceptionally difficult. The
l>iorncdienl resenrch community has mude extraordinary efforts to overcome
these many obstacles, but it appears unlikely that an effective vaccine
will he nvuiluble at finy time in ncar future.
At present nenrly 3,On,OOo cases of AIDS und over 30 million indi
vidllllis hllve been infected with Ill\' world wide. Although dwarfed in
IIIII[:llitlHlf> IIlld si[;llifieHIH'(, by tile Ill\' ('pi(kmic, several additional microbial
189
1I1;':lIts 1,lIve rccelltly becn i,jcntified us 11I11I1IIn puthogens. Cryptosporidia,
an lIei<l fllst [II'OIOZOlln of the coccidia order, hus been identified as a
reilltively com mOil cause of aClIte self-limited diarrheal disease of world
wide distri!>lIt ion AS well AS n mAjor <"'"lse of severe, protracted diarrhea
In immunocomprornised individuuls, most notably in victims of AIDS.
Itollgilly 4'1> of ,\IIlS plltients illlvc dellilitllting dillrrhea as a result of
cI'ypt osoporidilll i II fcc t ion, Tilere is liS yet no therapeutic agent that
is erreetivc Ilgllin,t Ihis newly idenlified ['Ilthogen.
384 ].:!!E ACQI1'll'ifLlMMUNOllEFICIENCY SYNllROME
INTHOllUCTION
1~0
The first reer)~lIlsed ellses of the disorder now known 8S aequired
inlilltiliodefieiency syndrome, os AI[)S, were reported in 1981. Soon many
Ilew ("lISp.s were dillgllo~pd HrTlOllg mnle homosexuals and intravenous drug
abusers and then among hemophiliac patients, reeeipients of contaminated
blood trllnsfusions, lind persons frolll IllIiti. For a time the number of
new cllses doubled about every six montlls. The largest number of cases
IIppc/ll'e<l in the grellt urbon centers, especilllly the New York city area,
Son fransisco and Los Angeles. Over 90 % were males.
By 1984, the etiologic IIgent, 8 new retrovirus had been identified,
IIlId II hlood test for IIlItihodies to the virus had been introduced to assure
II virtllllily safe blood supply. By ~Iuy 1987, epidem iologie studies had
disclose" lin IIllIrlllillg world wide distribution of the disease. Over 35,000
cllses Iwd been repOl"led ill the United StHtes, with 20,000 known deaths.
1\lthollr:h tlie <iollhlillg time of lIew ellses IIIIS lengtliened to 13 months,
I'efleeting bellllviourul changes among higli-risk groups and the success
of cOlltrol l1IeaSUI'es bused on the blood test, prospects for the next few
yeurs are staggering.
The wave of AIDS ill the United Stlltes, tlie Carribbean, and Latin
AmericII uppeRI's to be r\lnning behind thllt of Central Africa and ahead
of thlll of E\lrope lind Asi,.. Estimates of the number of infected indi-
vidunls world wide 1'lInr~c ns high /lS 5 to 10 million and of AIDS deaths
191
ill Afri"" ill tlie liulldrl!cls of tliuUSllllds. III Africu tile sex ratio of patients
with /\IIlS is 1:1, nod ileterosp\wli transmission predominates.
t\ few drugs IHlve heef} idpntifiC'd tlllit will hloek virul replication.
UIIl", azidoti'Y"liclille, lias silown beneficial elinil"ul effects in eurly studies.
,\ f('w vind proteins, (,sp0.(~illlly Oil£' tf'rllll'd .Gt~-----.!1_Q., have sllown antigenic
properties tlillt IIlIve encouraged vllccine development studies and preliminary
tests ill IlIlil1l11ls. Intensive, ongoing rcsl'lIJ"C'il centers on tile properties
"f till' viru" tile {1lltiIO[(f'IICsis of tile disen,e, its epidemiology world wide,
dI'lJ[~ dis('ovf'I'Y nnd cVllllIlition lind vnecillc d('velormellt. Public education
about risk avoidance needs to be intensified, lind developing countries
I",ed to institute cont"ols to Ilssure snfcty of tile,r blood supplies.
Definition
Tile 1"''IlIired immunodeficiency s,'ll(lrOllle (AIDS) was originally
OppOl'tlll\isli(~ illfc('tioll or as I(nposi's ~Hr(,OIllIl, or both; developing in
11 IH·pvioll'·dy 11C'llltllY individllnl with ('clll1ll1l' illlFlllJllodcficiency of unknown
co lise • AIlilougli this ellse definition stili "'rves some use in tracing the
spl'l~Hd of tile cpidelllie~ we no' .... kllow thllt n variety of clinical disorders,
beyond those III this initial surveillance definition, result from infection
witli tllC IllilillII' irnlllllnodeficie,wy Virus, 1111', tile etiologic agent of tile
syndrome. The elinienl outcomes of IIII' infections ronge from tile asympto-
Illllli," ('lIl'l'i(~r stolp to II gCIlC'[,lIli/,cd lymplllldC'lloplithy, which may be symp-
tOlllllt;(' (,111 JS-reilltcd ('oiliple, 01' .. \ 11(') 10 II rnpidly progressive disease
192
wilil lligil Illorl"lity frolll o[,porlllilislic infcdions or neoplasm (AIDS).
Netlrolog"ic iIlV()lv(,I1Il~lIt IS COflllllon. Ii(,CIIII5e tile full clinical spectrum
of IIIV illfedion is not yet known, new disorders related to lilY will
likely cOlltinlle to be identified.
Tile "'H'e of pAtients witil AIDS is at present largely symptomatic
"lid "'pportive willi spccific tilerapy for opportunistic infections and
i(nposj's SllreOll1fl. TilerApy for IIIV infection itself is experimental. The
life cyC'IJ' of IIIV reveliis ,,,verB I potcntial t''''gets for tllerapeutic agents.
Tile most pl'ominelit initial success Ilus been acllieved witll azidothymidine
wld(,1l is lin inllibitor of 1111' reverse trAnscriptnse, Azidotllymidine increases
slirvivnl unci prevents development of recllrrent opportunistic infections
wilen compurcd witli placebo in plltients witll AIDS who Ilad recently
recovered fr'om tlleir first episode of PnclImoeystis earlllli pneumonia.
Approximlltely :10% of tliose receiving Ai'.T for 6 months or longer required
fr'c'lucnt trllnsfusions. Current clinicAl triliis include testing of azidothy
midille ill plllients witil otliel' IllAnifeslutiolis of AIDS, as well as in earlier
sillges of IIIV infeetioll, silell liS AHC L\II)S relflted complex).
Ilceombinllnt alpllO 2a interferon IIIIS a direct antiviral effect in
vitro, PI'OhHbly ViH disruption of IIssembly of tile Virion. Irnmunomodulatory
ag('nts, suell as inte,'lcuhill-2 and cololly-stillllJiliting foetor are being tested
liS sillgle IIgelits 1I11r1 ill tlie lien I' future, ill cOlllbination with reverse trans-
(,I'iptllsc inliihitors SII('II ns nzidotllYlllidille. The feasibility of immune
193
reconstitution In A!IlS patients muy LJe Hssessed in syngeneic (identical
twin) bOlle marron! trllllsplontlltion with Hntiretrovirul therapy of the AIDS
patient, who then receives normal, but genetically identical, narrow stem
cells frolll his 01' her sibling, Ultimate therapy of AIDS will probably
I'cqulre several agents that aet on different parts of the life cycle of
IIIV liS well liS dl'ugs thllt foster imlllune reconstitution. To date, no
trclI!men! has been identified ns "cure" for ,\IDS, It is likely that bene
ficinl t11CI'IIPY woulll bc chronic, involving suppression of HIV for sufficiently
IOllg reriods of time to allow immune reconstitution to occur.
Persons who nrc infected witl) I11\' and are asymptomatic should
he vigol'ously counscled with respect to restl'ieting sexual behaviour that
could trllllsmit the virus, avoidance of dOllation of blood products, deferral
or pl'er.IlIIll<'Y, und ecssHlioll of intrHvcnOlis drug nbusc.
385 CANCEH
INTItOIHICTION
194
Cllnerl' still I'enlllins n fntnl <lisense IIIHI it is second only to heart
diseHse as H CHlISC of deoth in the most Advnnced country - U.S.A. and
fl""ollnts for 22% of nil <lenths. The most common cancers occur in
tile Illng In IIHlies, til" brenst in femnles nnll the colon and rectum in
ellcli sex.
t\lllIolli~1I I1l1ldl 1'('lllllillS to be 10111'1)1 IIbollt the fnctol's responsible
for vlll'intions of CHncer in \lIe genernl populntion, several environmental
CXI)()SIU'CS have been idcntified as cnuses of cancer. The evidence is
11I1S,,,1 Pl'illllll'ily on case-control studies (comparing the past experience
of pel'sons with nnd without a pnrticular cHneer) or cohort studies (following
up indiviclullls whose experiences Hnd clwracteristics are already defined).
'I'1"'I'c is II growing recognition, however, thnt most cancel's result from
tile combined effects of multiple exposurcs And susceptibility states. It
is gencl'lJlly thought that ctlJnullltivc environmental exposures, long latency
periods, and multistnge processcs account for the increasing risk of most
cnncel's wi I 11 ndvuncing ngc.
IJuring the Inst twenty yenrs tile trelltment of cancer has changed
markedly. With the introduction of new chemotherapeutic agents, more
t'rrt·(~tivf' I'lIdiothel'lIPY lind suq~ery tile tl'l'lItlll('ot of cunccr is becoming
inercllsillgly cffeetivc, ~lnny young [llltiC'llts with advanced malignant
195
diseuses I,ke Iympholllas, choriocorcinonlH, t"sticular cancer and childhood
I('ukcmiu (~un now be cured by (h'ug therapy with or without il'l'adiation.
lIowever, neopillsms like adenocarcinomas originating in the gastrointestinal
tract Clnd lung still remoin II clwllenge to the medical scientists of treat-
ment including drugs,
lIIethods,
lIere tile Ilope rests on the aggr~sive use of all
The first chemothcrClpcutics were introduced in the fifth decade
of lilis century, However, ini tiol results were not encouraging, These
drugs were nitrogcn mustard alltifoilltes, vinca alkaloids and co9!ticosteroids.
Only a portial response of short duration WBS observed and retreatment
met with the problem of resistance, The introduction of combination
chemothel'Opy for acute lymphocytic leukemia of childhood in the early
1%II's marked II turning point in the effective treatment of neoplastic
discase, Such combinations of chcmotherapeutic agents are now the stan
cillI'd for tile trclltment of most odvanced Cllncers,
The f"'inciplIl rlltionalc for combinlltion chemotherapy derives from
1111 nppreeiation of the reasons for fuilure of single agent treatment.
Even lile most responsive tUll10rs in the initial stages of treatment rapidly
nequire ,'csistance after drug exposure, Drugs ei ther induce resistance
or select ,'esistant mutllnts from nn initially heterogeneous tumor cell
populn tion. However, since the various Anticancer drugs have diverse
IIlC,,'llIlIlislllS of Hclion, cells resistHlit to olle II [;<'11 t might still be sensitive
Lo severn I ollIe,' d,'ugs, If drug, h1l\'e c1iffer""t non-overlapping toxicities,
196
CH(~il eall be lised ill full dosnge ill cOl1lbinntioll regimen. [)rug~ such
liS vilH'rist inc, pl'c<llli~OIlC. blcofllyeill Hud hcxlllllctllyJrnoilllllinc, which lack
bOlle 1ll11ITOW toxicity nre (lllrticulllrly vnlullblc for combination with myeJo- . ,
suppressive IIgents. 011 the busis of these principles curative combinations
hllve t)(>ell devised fOl' llcute lymphocytic IPukemia, The cure of advanced
IIIlIligllllllCY, wilcil possiblc, is prill1l1rily u"hi('v('ci with combination regimens.
The effcctive IIl1d snfc usc of C/lilCer chemotherapeutic agents
requires a funtilllllcntal uncicrstllnding of their action, interactions, pharma-
cokill('ties IIIHI toxicity of III nil. 1'1'0111 view poillt of El chemist ,structures
of Hlitincopltistic drugs Illust be thoroughly investigated and any similarity
III thcir struetw'cs or other structural featlll'es Illust be explored to design
ncw HnticHllcer dl'llgs.
Chcmical structure of clinicully useful alkylating agents and the
J'('lnlcd elnss of nitrosollrcs compounds HfC' displnycd here.
ALKYLATORS
~tcphlllllil Nit rogell mustard
cyclophosphll III ide
(~III 0"011111 ilu c i I
/CHz.-CHz.- CL
N
\CHZ- CH z- Cl
Clll,OltOETII Y LNITHOSOU ItEAS
I leri vo t ive It
i>is-chloroethylnitrosourea - C!l2
-CI12
-CI
Cyclohexylnitrosoureo (CCNU) D ~Iethykyclollexylnitrosoul'ea OCH3
(llielhyl ((,CNU)
( 'Iduro/.otoeill
197
Busulfan
198
('h"'lIists lind biologislS have \\'ork"" out IlIlli,,"ncer activity {in
, . 38ft 387 vitro) of (~OllipOlltlds IIHVlIl£" 5-fluo{'o urhed t pyrazole ) &. {3-phthalimi-
I I "d 388 'I " {ng- utllrlllli es ,qlllnazo one mOIeties.
F,'orn the above survey of ant ieaneer llgents, it is evident that
II,ere is no es IlIbl ishcd rc III t ion bet weC'n ehe In i ell I s I ruet ure and reaeti vi ty.
We report here synthesis of some moieties like jl-Iactam, quinazolone.
In our attcillpt to invcnt ncw onticanecr drugs we were extremely lucky
to enjoy over'whelming supporl from Nlltional Institute of Health, U.S.A.
As tile resul ts revelll sorne of our ('ornrounds hllve shown activity at
!,"lInliry level. ~Ioreover, in our humble opinion our project will inspire
s('ientists to synthesize new (lnticancer IIgents to cure this fatal disease.
199
A NTI-AIllS
, II' " 389, d ' d ' The IInll II 1I(~II\,lly test IS eSIg-ne 10 detect agents acting
"I lilly sInge of tI,C virus reproductivc cycle, Ti,e ussay basically involves
tI", Idllillg of '1',1 lymphocytes by 1111', The pl'oeedure is applicable to
ll)(! eVlIllUitioll of dnll~ cffeels 011 ill vitro illfcetiolls induced directly in
eullul'ed host cells by (,,,11 free IIIV-l or by coeulture with 119 cells ehroni-
c"lly infected with 1111'-1.
The IlSSIlY uses II newly developed telrllzolium reagent thut is meta-
J,t\il'lIlly reduced by villble cells to yield a soluble, coloured formazan
I"'()tiuct lIIeasured by convenlionlll eolourill1etric techniques,
~Ielllbolic rcouetion of ilITTI3-(4,5-dimetilyl lhiazol-2-yl)-2,5-diphenyl
I ell'lIzol illin brolll ide I .uld X'!'T (2,3 -bb( 2-lI1ct llOxy 4 -ni t ro-5-su]fophenyl)-5-
I(pilenylilluino) ellrbonyl) have been used 10 measure virus-induced cyto-
[llltiletic effects and cell proliferution, As the metabolic reduction of
MT'!' yields wllter insoluble formazlln product, it has been replaced by
XT'!' method which yields WIIICI' soluble form/1zlIn as the reduction product
of tile I'eng-ent XT'I', This method delcels drug induced suppression of
virlll eytoputllic effect by generation of the soluble formuzan in surviving
cells,
0'\ N-C-C-N= I II II .
- H 0 N
200
r NH I1lo
---~
N02. \11" '1("lrIlZolllllll \TT rornlflzan
Ti,e suitubility of VIII'ious T-Iymphocyte derived cell lines for inclus-
ion III the microculture XTT untiviral assay \\'1IS initially determined on
tlie hllsis of tlieir sensitivity to the lytic effects of IIIV-1 infection. Other
I'riterill were the nhilitips of the cells to l1lPtnilolicnlly reduce XTT to
1I1t'IISIII'lIblc qUlllltitics of XTT formllzon lind to sl,o\\' increased XTT formazan
pro(iI!('tion dlle to inhihition of virus infection t,y 1111 ngent.
IlltuGS
Stock solutions were prepared in IOO'\, D:IJSO nt the highest aehiev-
IIhle cOIH'cntl'lttioll fol' caell agent. Initinl dr"l: dilutions (1:400) resulted
in 11 mllximum culture concentration of 1>:llSO of 0.25% which had no
direct toxic effects on the cell lines lIsed or the IIIV-l infection. Com-
pOllnds used in these studies included 3'-uzido-3'-deoxy thymidine (AZT),
2' ,3'-dideoxy adenosine; 2' -3' -dideoxyinosine, 2'-3 '-dideoxycytidine, dextran
SlIlfllle, lIurill lriC'lIl'boxylic lIcid, suramin and cyclospol'ine.
202
'11'("<' ('lIleulutions are performed
Ly sitllpl(' lilll~HI' illtL'l'polntioll.
,\ZT ilrC tnkell llS stlllldard whicl, lire
O.186...l1M
1 Y 1 ...lIM
= 11)2~
('ollsitlcl"ing lilt' scope of lilis tl,esis. we iluve incOI'porated limited
dlltll of tile test rcsults. lIe have descriiJed here drug concentration
;ll Wlli('" IJlllXirllUrtl ,'c'ponsc jC\ fI{'hic\'C'd. [lith the help of this data we
ll,rvc tr'i"cl to "xplor'(' 'true'tll"" '1<'ti"it,' r('llItinn if it exists lit nil.
203
ANTI-CANCEH ACTIVITY
The in vilro anticancer activity of the synthesized compounds
WIIS ,,"rried Ollt by Ille scientists of National Cancer Institute, Bethesda,
U.~.A. Different llspec-ts of this "in vitro" testing are thoroughly dis-
cllsscd hy t he len /'lwei I en III of Ill'. ,\ nne ~I ollks 13 !JtJ A et II. • brief introduct-
ion is given here.
To explore nnticnncer nctivity of test compounds. at primary level
II totnl of fitJ II Ilfl II II. tlllllor cell lin('s derived from seven cancer types
(lung, colon, melanoma, renal, ovariun, brain and leukemia) that adequately
meet llIinimulfl'lulllity flSSUrllnce critcrill. which are adeptable to a single
growth medium and which have reproducible profiles for growth and drug
sensitivity are sclected for pilot sCllle screening operations. From 1993
NCI has introduced t IVO more cancer types which are prostate and breast
cnnecl's.
A series of 175 known compounds, comprised of commercially
nHll'keted anticancer IIgents, investigationlll anticancer agents and other
cHIHlidn t e lin tit U 11101' ligen ts Are se lee t ('d for pilot screening studies.
For cellulnr growth and viubility in the primary screen, three alter-
notive methods ore used. Two are n.etal>olic assays which are known
LIS MTT and XTT assays. In these methods colourless tetrazolium salt
(MTT or XTT) yields coloured formflzlln ,iPrivative in proportion to viable
celi number. The formflzans flre measured conveniently in an automated ..
204
eolorilllctcr. TI,c ~ITT assay is IJased on Ille lIlellibolie reduclion of 3-
(4,5-<iimelllyl Illiuzol-2-yt)-2,5-diphenyl lelruwliulII bromide (MTT). The
product of metabolic cellular reduction IS un insoluble formazan which
is dissolved in D~ISO prior to colourirnetry. To eliminale this stage of
solubilization the method involving XTT is introduced. XTT (2,3-bis(2-
me t hoxy-4 -II i t ro-5-sul fophenyl )-5-[ (pheny 10 m i no) carbony I 1 2-11 tetrazolium
hydroxide) on metllbolic rccluction gives wllter soluble formazan allowing
dired rending of optieal density.
The thin! PI'OCCdlll'e is of sulforho<illllline II (SHII) assay. SHU is a bright
pint< nlliollic dye which in dilute lIt'etie Bcill billds eleetl'ostatieally to
till' hasie IIlIlino lIeids of trichloroacelic liPid fixed cells. As the results
(iPscrihed in tlli, tllesis IIrc obtllincd by this proeedure, a brief description
is given liere.
All ccll lincs Ilre inocuillted into II scries of stllndard ~6-well miero
titre plotes on dey 0, in tile majority of cuses at 20,000 cells/well, then
preincubated in absence of drug for 24 Ilours. Test drugs are then added
ill five tenfold llilutions starting from the Ilighest soluble concentration
1111<1 incubuted for a further 48 Ilours. Following this,adherent cell cultures
BI'e fixed in situ by adding 50J.L of cold 50,\; (wt/vol) trichloroacetic acid
('rCA) (finlll conc. 1(1% TeA) and incubating for 60 minutes at 4°C.
The supernatant s then discarded, and the plutes are washed five times
wi til deiollized wllter find dried, One hundred rnicrolitres of SRB solution
(0.·1% wi/vol) in 1% ucctic neid} is uddC'd to clI('h microtitro woH, and
111l' CHILli!"!' is illculJIIlCU ror 10 minutes at rooll\ tClllperAlure. Unbound 81tH
205
is removed by wlIsllilig five times with I'\, lIectic Acid. Then the p1ates
me air-dried. Bound stain is SOlubilized ill Trb buffer and the optical
d('nsities Ill''' reud on fin uutomnted spectrophotometer pillte reader at
u single wuvel('llgth of 515 nm.
IlII til Cu leuln t ions
Unprocessed opticlil density dutn frolll elleh microtitre plate are
1I11tomlltically trHnsferred frolll the pillte reuder to a microcomputer,
where thc bllckgJ'Ound optienl density mCIISlIrempnts (i.e., complete medium
pillS stain minus cells) nre substracted from the uppropriate eontrol well
vulue, lind wllere the IIppro()['ilite drug-illllnl; nlPnsurements (i.e. complete
medium plus test compound dilution plus stnin, minus cells) are substrated
frolll the npproprinte test lI'ell volues. The volues for mean ± 5D of
dnta fl'OIll replicate wells nre calculnted. Dnta are expressed in terms
of % T/C [(Oil of trented celis/Oil of control cells) X 100), as a measure
of cell viability and survival in the presence of test materials. A measure
is !llso mlldc of thc cell popuilltion density lit time a (the time at which
drugs are added) from two extra reference plates of inoculated cells
fixed with TCA just prior to drug addition to the test plates. ThUS,
there are three measurements control optical density (C), test optical
density ('1') lind opticlIl density at time ZCro (To).
lIsing these Illensurements. ccllullir respollses eRn be calculated
for gl'owtll stimulatIOn, for no dl'ug effect. lind for growth inhibition.
If T > To the cnlculntion is 100 X (T-To)/(e-To»). If T (To, cell killing
,.
206
IIl1s OI'('III'I'ed lind clln be elli<'IIluted fro III 1111) X fer-To}/To]. Thus, for
cHell drug-cell line eOIllhililltioll, H dose respollse curve is generated and
thre" levels of effect fire calculated. Growth inhibition of 50% (GJ50
)
is culcullttcd from lOU X [(T-To}/(C-To)] = SO wllich is the drug concen
trntion causing [J 511~ reduction in the net protein increase in control
cells 'itlring the drug incuiJat ion. The drug eoncentration resulting in
totnl gl'Owth inhibition (TGI) is ealcuillted froll1 T = To where the amount
of pl'otein ot tile end of drug incublltion is equul to the Ilmount at begin-
Iling. Tile finnl cilicuilltion of LCSO
is the concentration of drug cllusing
II 50~ reduction in the lIleusured protein ut the end of the drug incubation,
compmed witll tllat at the beginning, indicating II net loss of cells following
clrllg treatment. LCSO
is calculated from 100 X [(T-To}/To] = -50.
As described in tile procedure of lint iClincer screening. each compound
is tested oguinst 60 cell lines Ilt five dlffen'nt concentrations, complete
dj~('IISsi()1l of tlie !'('sults obtllillPd is b(,~·Olld tile scope of this thesis.
Moreover, tile objectivc of tile I"'esent project is to explore anticancer
udivity of some potentilll cliemotlier/lpcut ies lind to correlate it with
the strue!ure. Therefore, we have limited our result discussion to growth
inhibition llgninst different cell lines lit diffcl'pnt concentrations. Then
we "nve tried to evnlilutc uctivity of u .'cries of compounds against a
pllrticullir type of ClIllecr or cell lille.
39 1 Allti"""'"rilll ~lIseeptihility Te~tillg
207
'I he st"dy hilS heen coneiucted ,,,,cor(]illg to tile melhod adopted
hy H. ('f'lIi<'kshHllk ('t Ill. Nlltripnt II gil I' 1'1'011, IV liS melted in a water-
"alII IIl1d cool"d 10 4')"(: willi g('ntle slHlking to bring Ilbout uniform cooling.
It WIIS ill(H'ulllted witll 11,'i-0.6 ml of 18· 2·1 Ill' old culture IIscptically and
mixed well by gentle silnking before pourlllg on the sterlized petri dishes
2" 1111 in ellch pelri dish). The poured Inllterilll WAS allowed to set
(1.5 hr) Ilnd ther'cllfter' Ihe "cups" (10 mm diameter) were made by punching
into tile lIgnl' slIrrnce wi til II sterile eork borer Bnd scooping out the punched
I'lll't of the ugar'. Into tilese cups were added 0.1 ml portions (100 .,ug)
of tllp test eoml'ounds in 1J.~1.F. willi tire Ilelp of sterile syringe. The
drug solutioll IVIlS allowed to diffuse inlo tile mediul11 for ubout an hour.
Tire pilltes were incubated lit 37°C for ·18 hr. And the width of growth
inhibition zone noted. Chlor'ollrnphenicul I\'IlS used as standurd drug and
" s"lv('ttl control IVIIS IIlso run to kttow the lIetivity of solvent.
The COIIlPOIHHIs lire tested 1Il-{llillst stlilld/lni struill of ~~eobHcterilllT1
The com[>olHld b di"olvcd In LJI\1F und lidded in
Lowetlsteitl-Jetlse's medium so thut final cotlcentration of the compound
in 5.-ug/ml, 3U "ug/rnl "tld IUD ..Ilg/ml of mediurn.
'I lie eOfllpollIHI is lidded before ills-piss-tltion, the chemical containing
tl",<liltlll is tlisll'ibutctl in 7 till IImollnt 1tl Set'ew cupped I\1cCartueeyls
Illbr's. .1\11 tllP 11thes itlspisslllC'(1 itl slopping positiotl lit BUoC for 45 minutes.
208
J\i2 Ti,e mediulll is ilioeuilited IIccordilig 10 tlic re('olilmendulion of W.II.O.'
Tlie inoculum for Ihe susceptibility tests hos been prepared by
IIddill[!; IIpproximlitcly 2.0 mg of growth f"om the primary culture on a
loop to 5 ml ste"ile distilled Wllter in Il 7.0 rill ",,-eVi copped tube together
with 6 x :1 "'''' glnss bends. The tubes slHlken rneclionicnlly for one minute
and a full 3 mm loopfull of s"spension illoculated onto each slope. Dupli-
cnte slopes from elleh compound inoculntcd nnd tlie drug free control
slopc also set up with cnch test. The t IIlles incu!>"ted at 37°C and the
results of tlie tests relld IIfte,' six weeks.
:!:1~~:rI_t:l~; OF ~ t:lTII!!2CTEHI:' L, ~ NTITI!IIEllCULAH,
ANTI-IIiV ANI> ANTICANCEH ACTIVITY
I Ill{ '\N'IIIl,\(:TLHL\J. ,\cTI\TJ'Y OF ('O:-II'OlINIlS:
/,011(> of (;rowth Inhihition in min.
209
Leoli S.aureus Salmonella
(1) Solvent control 1l.~I.F.
(2) Stll",ll\I'd I )rllg Cilloroo mpilenical
----
I 'i
24
Para typhi
12 15
27 25
A
(1) Indicates no inilibitory crfect, i.e. compound is not
effective.
(2) Indicates inilibitory dfed, i.e. compound is effective.
Cll Solvent control nnd pillin control indieatcs tile grow til of bacteria
IIlId tillS 110t been recorded ill tl1(' tllbl('s.
('I) Strain IIsed for Ilntitllbcrclllnr stlldy is 1137Hv'
(;}) Stll1le standard drug has show II Iletivily Ht following concentration:
Isonillzide 2 ,"lIg/111 I
~trC'plolllycin
Hephampicine
Elhll,"blltnl
25..ug/ml
8 Ulg/ml
ANTICANCER ACTIVITY
TYPE OF CANCER
Lukemin
Non-small cell I.ung Cancer
Small cell Lung Cancer
Colon Cancer
CNS Cancer
Melanoma
Ovarian Cancer
Renal Cancer
Breast Cancer
Prostate Cancer
210
CODE
A
B
C
D
E
F
G
H
I
J
Sr. Ar No.
Teble-I
ANTILBACTERIAL AND ANTITUBERCULAR ACTIVITY OF SOME 2-(N-SUBSTITUTED CARBAXAMIDO METHYL THIO)-5-BENZYL
1,3,4-0XADIAZOLE
21 1
Antibacterial activity Antitubercular Zone of inhibition in mm activity.
Salmonella Conc. in J.u~ I ml. E.coli S.aureus tY[lhi
Para A 5 30 ------------------------------------------------------------------(1) (2) (3) (4) (5) (6) (7) ------------------------------------------------------------------
1. -c H 20 18 19 + 6 5
2 . -2-NO -c H 18 17 23 + 2 6 4
3 . -3-NO -c H 18 17 17 + . + 2 6 4
4. -4-NO -c H 18 22 17 + + 2 6 4
5. -2-CH -c H 20 16 16 3 6 4
6 . -3-CH -c H 20 15 18 3 6 4
7 . -4-CH -C H LO 20 17 + 3 6 4
8 . -3-0CH -c H 2L 15 18 + 3 6 4
212
------------------------------------------------------------------( 1 ) (2) (3) (4) ('i) (6) (7) ------------------------------------------------------------------
9 . -4-0CH -c H 20 18 17 + 3 6 4
10. -4-Br-C H 6 4
20 1') 17 +
1l. -2-CL-C H 2 1 1') 18 6 4
12. -3-CL-C H 17 1 7 20 + + (, 4
13. -4-CL-C H 20 20 17 + + 6 4
14. -2-0C H -C H 17 20 18 + 2 ') 6 4
1 5 . -4-0C H -C H 17 18 17 + 2 5 6 4
16. -2.4-(Cl) -c H 17 1) 20 2 6 3
1 7 . -2.4-(CH ) -c H 20 17 17 + + 3 2 6 3
1 !l . -2-NO -4-Cl-C H 18 20 17 + 2 6 3
19 . -2-Cl-4-NO -C H 15 17 20 2 6 3
TABLE 2
ANTI AIDS & ANTICANCER ACTIVITY OF SOME 2-(N-SUBSTITUTED CARBOXAMIDO METHYL THIO)-5- BENZYL-1,3,4-0XADIAZOLES
No. Ar Anti HIV activity Anti cancer activlty Infected uninfe'-Dose Responce Res. molar
% growth typeOf Cell G1 50 TGT -LC50 cancer llne
(1) (2) (3) (4) (5) (6) (7) (8) (9 ) (10) en)
1. C6H5 10.38 98.34 2.10x10- 5 Not Noteworthy
2. 4.N02-C6H4 16.85 48.32 9.70x10- 5 Not Noteworthy
3. 3-N02-C6H4 10.77 108.68 3.10X10- 6 Not Noteworthy
4. 2-CH3-C6H4 15.84 31.82 2.80xl0 -4 Not Noteworthy
5. 3-CH3-C6H4 9.74 102.48 1. 30xl0- 6 Not Noteworthy
6. 4-CH3-C6H4 9.16 89.20 1.80xl0-6 Not Noteworthy
7. 3-0CH3-C6H4 12.28 95.74 1.00xl0 -5 Not Noteworthy
8. 4-0CH3-C6H4 11.01 91.19 1.00xl0-6 Not Noteworthy
9. 2,4-(Cl)2-C6H3 11. 70 80.56 6.60xl0- 5 Not Noteworthy
10. 2-CI-C6H4 13.35 90.42 1.40xl0 -4 Not Noteworthy
11. 3-CI-C6H4 33.32 17.29 1.00xl0-4 Not Noteworthy
12. 4-CI-C6H4 37.68 43.62 1. 00xl0- 4 Not Noteworthy
·13. 2-0C2HS-C6H4 10.63 103.82 1.90xl0 -7 92 C DMS-114 1.67xl0-5 3.24xl0 -5 5.97x10- 5
87 D COLO-205 2.05xl0- 5 -5 6.S0x10- 5 N 3.65xl0 >-
"" 87 G OVCrIR-3 1. 72xl0- 5 3.27xl0 -5 6.23x10- 5
81 H CAKI-l 2.05x10- 5 3.76xl0- 5 _5 6.88xl0
----------------------------------------------------------------------------------------------------------------------(l) (2) (3) (4) (5) (6) (7) (8) (9) (10) ( 11) ----------------------------------------------------------------------------------------------------------------------
14. 2,4-(CH3)2-C6H3 11.54 94.44 1. 40x10- 6 Not Noteworthy
6 15. 2-N02-4-C1-C H3 9.52 96.69 2.00x10 -6 100 C
100 E
100 H
99 F
DMS-273 1.97x10-5
XE-498 1. 75x10- 5
ACHN 1.26x10-5
SKMEL-28 1. 55x10- 5
3.39x10- 5
3.13x10- 5
2.52x10-5
2.9Ox10- 5
5.84x10- 5
5.59x10- 5
5.02x10- 5
5.43xlO- 5
N ...
Sr. No.
(1)
1.
2.
3.
4.
5 .
6.
215
Table -3
ANTIBACTERIAL AND ANTITUBERCULAR ACTIVITY OF SOME 2-(N-SUBSTITUTED CARBOXAMIDO METHYL THIO)-5-(4--(4-CHLORO BENZYLIDINE)AMINO PHENYL -1,3,4-0XADIAZOLE
Ar.
( 2 )
-C H 6 5
-2-C1-C H 6 4
-3-CI-C H 6 4
-4-CI-C H 6 4
-2-NO -C H 2 6 4
-3-NO -C H 2 6 4
Antibacterial activity Salmo
E.coli S.aureus nella typhi Para A
( 3 ) ( 4 ) ( 5 )
19 12 15
20 12 18
17 19 16
18 13 15
18 20 15
20 15 15
Antitubercular activity again -st H R conc.
37 v 30JuJlml IOO;q,
ml
( 6 ) ( 7 )
+
+
+
216
-------------------------------------------------------------(1) ( 2 ) ( 3 ) (4 ) ( 5 ) ( 6 ) (7) -------------------------------------------------------------
7 . -4-NO -c H 18 13 18 + 2 6 4
8. -2-0C H -c H 19 13 17 + + 2 5 6 4
9. -4-0C H -c H 18 13 15 2 5 6 4
10. -4-Br-C H 22 13 16 +
6 4
11. -3-CH -C H 18 17 15 + + 3 6 4
12. -4-CH -C H 19 13 16 + 3 6 4
13. -2-0CH -C H 17 12 15 + + 3 6 4
14. -3-0CH -c H 17 16 15 + 3 6 4
15. -4-0CH -c H 18 14 15 + 3 6 4
16. -2,4-(Cl} -C H 16 13 22 2 6 3
17. -2,4-(CH } -C H 13 16 19 3 2 6 3
18. -2-NO -4-CI-C H 15 16 17 2 6 3
19. -2-Cl-4-NO -c H 14 15 18 2 6 3
TABLE :4 --ANTI AIDS & ANTICANCER ACTIVITY OF SCME PHENYLJ-1,3,4-0XADIAZOLE
Z-(N-SUBSTITUTED CARBOXAMIOO ME1HYL lliIO)-5-[4-(4-QfLORO BENZYLIDINEJ AMINO
--------------------------------------------------------------------------------------------------------------------------No. Ar Anti HIV activity Anti cancer activity
Infected uninfe. Dose Responce Res. molar
% growth type of Cell GI sO TGI LC50 cancer lme --------------------------------------------------------------------------------------------------------------------------(1) (Z) (3) (4) (5) (6) (7) ( 8) (9) (10) (ll) --------------------------------------------------------------------------------------------------------------------------
1. C6H5 7.89
2. 4-NOZ-C6H4 1l.54
3. 3-NOZ
-C6H
4 9.28
4. Z-NOZ-C6H4 12.56
5. Z-CH3
-C6H
4 10.79
6. 3-CH3
-C6
H4
10.83
-7 104.31 1.20xlO Not Noteworthy
90.57 4.60xlO-6 100
100
100
100
100
105.62 4.60xlO- 7 100
97
96
89
B
C
D
F
H
F
C
D
G
llZ.99
79.63
2.40xlO- 6
6.80xlO-6
Not Noteworthy
97 D
99.09 6.80xlO-6 100 C
100 D
HOP-18
Dlli-114
HCC-2998
UACC-6Z
ACHN
NL-9 MEL
DMS-114
HCT-1l6
SK-OV-3
HCT-116
NCI-H-23
KM-12
1.64xlO-s 2.99xlO- 5 5.47xlO- s
3.3lxlO-6
1.25xlO-5
9.83xlO- s
1.54x10-5
1.46xlO- 5
2.50xlO- 5
Z.5lx10- S
2.83x10- 5
3.82x10- s
5.00xlO- s
4.63x10- s
s.36xlO- s
1.sOxlO-5 Z.83xlO- s s.3ZxlO- s
1.OZxlO-s Z.Z3xlO- s 4.85x10- s
1.40xlO-s Z.Z7xlO- S 5.36xlO- s
1.11xlO-s Z.4sxlO- s 5.4ZxlO- s
1. 56x10- s -5 Z.94xlO 5.s3xlO- s
7.s4xlO-6 Z.04xlO- 5 4.sZxlO- s
1.08xlO- s Z.26xlO- 6 4.76xlO- s N
-.J
------------------------------.-----------------------------------------------------------------------------------------(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (ll ) ---------------------------------------------------------------------------------------------------------------.----------
100 E
100 F
100 H
97 G
7. 4-CH3-C6H4 11.63 108.54 2.20xlO -8 100 D
100 F
99 B
99 E
98 H
8. 2-CJCH3-C6H4 9.69 95.43 6.50xlO -6 Not Noteworthy
9. 4-0CH3-C6H4 10.58 96.82 3.40xlO -6 100 B
98 C
94 H
10. 2,4-(C1)2-C6H4 11.58 100.35 1.40xlO -5 76 F
62 E
53 C
XE-498 1. 35x10 -5
LOX IMVI 3.43x10-6
AOIN 1.07x10- 5
OVCAR-3 1.l7x10-5
HCT-116 1.57x10- 5
SKMEL-5 1.47xlO-5
HOP-18 1. 74xlO -5
U-25l 1. 94xlO -5
RXF-393 1. 90xlO- 5
NCI-H-322M 1.66xlO -5
DMS-273 1. 93xlO -5
ACHN 1. 67xlO -5
UACC 257 1.95xlO-5
U-251 1. 80xlO- 5
DMF-1l4 1.57xlO-p5
2.63x10 -5
1.56x10-p5
2.52x10 -5
2.42x10 -5
2.91X10- 5
2.78xlO- 5
1. 74xlO-5
3.36x10- 5
3.32x10 -5
3.02xlO -5
3.37xlO -5
3.11x10 -5
3.74xlO -5
3.87x10 -5
3.87x10 -5
5.13x10- 5
3.95x10- 5
4.75xlO- 5
5.01x10- 5
5.39x10- 5
5.28xlO -~
5.63xlO -5
5.83xlO -5
5.83xlO- 5
5.49x10 -5
5.87xlO -5
5.80xlO -5
7.17x10 -5
8.30x10- 5
9.49x10-p5
N .... 00
--------------------------------------------------------------------------------------------------------------------------(1) (2) (3) (4) (5) (6) (7) (8) (9) (10 ) (11 ) --------------------------------------------------------------------------------------------------------------------------
11. 2-Cl-C6H4
12. 3-Cl-C6H4
13. 4-C1-C6H4
10.85
9.87
9.89
101. 97
106.46
100.37
-7 4.70x10
-7 1. 50x10
-8 2.80x10
Not Noteworthy
100 D
100 H
97 B
97 E
100 D
100 H
99 B
95 F
52 A
HCT-116 1.29x10-5
CrlKI -1 1. 19x1O- 5
A-549/ATCC 1.88x10 -5
SF-295 1. 88x10- 5
HCT-116 7.75x10 -6
TK-10 1. 84x10- 5
NCI-H-322-M 1.60x10 -5
SKMEL-5 5.69x10-6
MJLT-4 1.12x10 -5
2.55x10- 5
3.32xlO- 5
3.31x10- 5
3.36x10- 5
2.02x10 -5
3.24x10 -5
2.96x10- 5
1. 97x10 -5
3.28x10 -5
5.05xlO- 5
5.76x10- 5
5.83x10 -5
5.99x10 -5
4.50xlO -5
5.70x10 -5
5.48x10 -5
4.62x10 -5
9.63x10 -5
N -<D
220
ANTIBACTERIAL AND ANTITUBERCULAR ACTIVITY OF SOME 2-(N-SUBSTITUTED CARBOXAMIDO METHYL THIO)-5--(4-ACETYL AMINO PHENYL)-l, 3, 4-0XADIAZOLE
Sr. Ar. No.
(1) (2)
1. -C H 6 5
2 . -2-Cl-C H 6 4
3. -3-Cl-C H 6 4
4. -4-CL-C H 6 4
5. -2-NO -C H 2 6 4
6. -3-NO -c H 2 6 4
7 . -4-NO -C H 2 6 4
8 . -2-0C H -C H 2 5 6 4
Antibacterial activity Zone of inhibition in mm
Salmonella E.Coli S.aureus typhi
Para A
(3) (4) (5)
20 16 17
20 16 17
17 14 15
20 17 16
17 15 15
18 17 15
20 15 16
20 1 5 1 7
Antitubercular activity against H R conc.in
37 v foa1ml.
30 100
(6) (7)
+
+ +
+ +
+
+
+ +
221
----------------------------------------------------------------
(1) (2) (3) (4) (5) (6) (7)
----------------------------------------------------------------
9 . -4-OC H -C H 18 16 22 2 5 6 4
10. -4-Br-C H 18 15 20 + 6 4
1l. -3-CH -c H 17 14 20 3 6 4
1 2 . -4-CH -C H 18 17 22 3 6 4
13 . -2-0CH -C H 17 L2 18 + 3 6 4
14. -3-0CH -C H 17 30 21 + + 3 6 4
1 5 . -4-0CH -C H 17 15 20 + + 3 6 4
16 . -2.4-(Cl) -C H 1 7 20 20 + 2 6 3
17 . -2.4-(CH ) -C H 20 15 18 + + 3 2 6 3
18 . -2-NO -4-Cl-C H 18 L2 17 2 6 3
19. -2-Cl-4-NO -C H 20 20 17 2 6 3
ANTI AIDS & ANTICANCER ACTIVITY OF SCME OXADIAZOLE
No. AT Anti HIV activity IiiIected lll1inre:-DOse Responce Res. molar
(1) ( 2) (3) (4) (5)
1. C6H5 10.21 96.14 3.50x10
2. 4-N02-C6H4 10.50 92.57 3.80x10
3. 3-NOZ-C6H4 10.15 67.16 5.50x10
4. Z-NOZ-C6H4 9.70 1l0.06 2.00x10
5. Z- CH3-C6H4 11.44 30.87 3.90x10
6. 3-CH3-C6H4 9.83 98.78 6.90x10
7. 4-CH3-C6H4 10.09 101. 54 8.90x10
TABLE : 6 --2-(N-SUBSTITUTED CARBOXAMIOO METIfYL lliIO)-5-(4-ACETYL AMINO PHENYLJ-1,3,4-
Anti cancer activity % growth type of Cell GI 50 TGI
cancer lIne
(6) (7) (8) ( 9) (10)
-7 93 D HCT-1l6 1. 66x10 -5 3.11x10- 5
82 F LOX 1MV1 1. 96x10 -5 3.64x10 -5
70 B NCI-H-522M 1.69x10-5 3.55x10- 5
-7 100 D HCT-1l6 2.58x10 -6 9.43x10 -6
99 F LOX 001 1.06x10 -5 2.42x10 -5
97 C DMS-273 1.65x10- 5 3.04x10 -5
94 H RXF-393 1.96xlO -5 3.46xlO -5
-7 Not Noteworthy
-6 Not Noteworthy
-4 Not Noteworthy
-8 Not Noteworthy
-7 Not Noteworthy
LC50
( ll)
5.84x10-5
6.75x10- 5
7.46x10 -5
3.08x10-o
4.76x10 -5
5.62x10 -5
6.10xlO- o
N N N
--------------------------------------------------------------------------------------------------------------------------(1) (2) (3 ) (4 )
8. 3·OCH3-C6H4 Under Testing
9. 4-0CH3-C6H4 Under Testing
10. 2,4-(Cl)2-C6H3 Under Testing
11. 2-Cl-C6H4
12. 3-Cl-C6H4
13. 4-Cl-C6H4
Under Testing
Under Testing
Under Testing
(5) (6) (7) ( 8)
100 E U-2S1
100 D KM-20 L2
98 H UO-3I
Repeat testing at primary stage
88 D Hcr-116
64 F MAlME 3M
50 H SNI 2C
Not Noteworthy
Not Noteworthy
Not Noteworthy
(9) (0)
1.7lx10-s 3.08x10- s
1.69x10- s 3.06xlO- s
1. 8sxl0- s 3.27xlO- s
2.20x10 -5 3.8Ix10- s
1.64xI0 -5 3.62xlO- s
2.40XIO- S 4.S0xlO-s
(11 )
5.5sx10- s
s.53x10 -5
5.78x10- s
6.60x10 -5
7.98xlO- s
1.00x10- 4
N N
'-"
Teble-7
ANTIBACTERIAL AND ANTITUBERCUl.AR ACTIVITY OF SOME 1-ARYL-3-CHLORO-4-(INDOL-3-YL)-2-0XO AZETIDINES
Sr. Ar. No.
(1) (2)
1. -C H 6 5
2. -4-8r-C H 6 4
3 . -2-C1-C H 6 4
4. -3-C1-C H 6 4
5. -4-C1-C 11 6 4
6. -2-CH -C H 3 6 4
(IV)
Antibacterial activity Zone of inhibition in mm
Salmone lla
E.coli S.aureus fYPhi Para A
( 3 ) ( 4 ) ( 5 )
17 22 22
18 20 18
20 18 17
20 19 15
19 12 15
20 16 15
"
224
Antitubercular activity against H R conc.
37 v
30
( 6 ) (7)
+
+ +
+ +
+
+ +
+ +
zzs
---------------------------------------------------------------( 1 ) ( 2 ) ( 3 ) ( 4 ) ( 5 ) ( 6 ) (7) ---------------------------------------------------------------
7. -3-CH -c H 19 13 17 + 6 4
8. -4-CH -c H 22 20 18 + 3 6 4
9. -2-0CH -c H 23 16 20 3 6 4
10. -3-0CH -c H 22 20 17 + + 3 6 4
11. -4-0CH -C H 18 17 17 3 6 4
12. -2-NO -c H 18 15 17 2 6 4
13. -3-NO -c H 18 17 18 + + 2 6 4
14. -4-NO -c H 18 19 19 + 2 6 4
15. -2,6-(CH ) -c H 17 15 16 + + 3 2 6 3
16. -2,4-(Cll -c H 18 17 15 2 6 3
17. -4-0C H -C H 15 13 18 2 5 6 4
18. -2-Cl-6-CH -c H 13 15 14 + 3 6 3
19. -2-CH -4··NO -c H 17 18 17 3 2 6 3
20. -2-NO -4-Cl-C H 14 14 13 + 2 6 3
TABLE : 8
ANTI HIV & ANTI CANCER ACTIVITY OF SCME l-ARYL-3-CHLORO-4-(INIXlL-3-YL)-2-0XO AZETlDINES
No. Ar Anti HIV activity Infected uninfe. Dose Responce Res. molar
(1) ( 2) (3) (4) (5)
l. C6H5 9.37 102.10 1. 00xl0 -6
2. 2-CI-C6H4 10.97 97.66 1. 20xl0 -6
3. 3-CI-C6H4 12.77 104.01 2.80x10 -7
4. 4-CI-C6H4 20.12 15.33 6.50x10-6
5. 2-0CH3-C6H4 11.27 74.26 1. 50x10 -6
6. 3-0CH3-C6H4 10.09 93.65 8.00x10 -6
7. 4-0CH3-C6H4 10.88 113.28 4.90x10 -8
8. Z-NOZ-C6H4 9.65 69.66 2.80xl0 -5
Anti cancer activity % growth type of Cell GI SO TGI LC50 cancer llne
(6) (7) (8)
Not Noteworthy
Not Noteworthy
Not Noteworthy
100 E U-251
98 B NCI-H322 M
95 F MAlME-3M
94 H TK-10
88 D HCT-1l6
71 G OVCAR-3
Not Noteworthy
Not Noteworthy
Not Noteworthy
Not Noteworthy
(9) (10)
1.30x10- 5 2.57xl0 -5
1. 64x10- 5 3.03x10 -5
1. 25x10- 5 2.56x10 -5
1.98x10- 5 3.48xl0 -5
1. 38x10- 5 2.82xl0 -5
1. 76x10- 5 3.61x10 -5
(1)
5.07x10 -5
5.85x10 -5
5.23x10 -5
6.11x10- 5
5.77xl0
7.23x10
-5
-5
Contd ...
N N 0-
--------------------------------------------------------------------------------------------------------------------------(ll ( 2) (3) (4) (S) (6) (7)
9. 3-N02-C6H4 7.46 91. 85 3.30xl0 -7 100 F
89 H
79 B
77 E
10. 4-N02-C6H4 8.09 94.42 1. SOx10-6 Not Noteworthy
11. 2,6-(C1)2-C6H3 7.S2 69.41 2.60xlO- S Not Noteworthy
12. 2,4-(C1)2-C6H3 9.29 83.64 2.30x10- 6 Not Noteworthy
(8 ) (9) (10)
MALME-3M 2.36xl0-6 1.41xI0
RXF-393 1. 29x10- 5 2.70x10
LXFL-S29 6.2Sx10 -6 2.04x10
SF-29S 1. 78x10 -S 3. SlxlO
(ll )
-5 3.75x10
-5 S.63x10
-5 5.S9x10
-S 6.91x10
-5
-5
-S
-5
N N ....,
228
Teble-9
ANTIBACTERIAL AND ANTITUBERCULAR ACTIVITY OF SOME 1-(2-HYDROXY BENZOYL AMINO)-4-ARYL-3-CHI.ORO-2-0XO AZETIDINES
Sr. Ar No.
(1) (2)
1. -C H 6 5
2 . -2-0H-C H 6 4
3 . -3-0H-C H 6 4
4. -4-0H-C H 6 4
5 . -4-0CH -C II 3 6 4
6 . -3-NO -C H 2 6 4
,co NII].= r:., '011 0 11
( II T)
Antibacterial activity Antitubercular Sal monel activity against
E.coli S.aureus -la typhi H R cone
( 3 ) (4 )
19 12
20 12
17 19
18 13
18 20
20 15
_Pa_r_a ~ __ ~3~7_v~ ______ ___
( 5 )
15
18
16
15
15
15
30.LLJ/ 100 .l4J/ml ml
( 6 ) (7)
+
+
+
229
---------------------------------------------------------------(1) ( 2 ) ( 3 ) (4 ) ( 5 ) ( 6 ) (7) ---------------------------------------------------------------
7 . -4-NO -c H 18 13 18 + 2 6 4
8. -2-Cl-C H 19 13 17 + + 6 4
9. -3-C1-C H 18 13 15 6 4
10. -3-0CH -C H 22 13 16 + 3 6 4
11. -CH=CH-C H 18 17 15 + + 6 5
12. -3-0CH -4-0H-5-I-C 1\ 19 13 16 + 3 6 3
13. -2,4-(OCH ) -C H 17 12 15 + + 3 2 6 3
14. -C H 0 17 16 15 + 5 4
15. -2-0H-5-Br-C H 18 14 15 + 6 3
16. -2-0H-3,5-(br) -C H 13 17 12 2 6 2
17. -4-CH -C H 12 10 16 3 6 4
18. -3,4,5-(OCH ) -C H 14 15 13 + 3 3 6 2
19. -2-0H-C H 16 10 14 + 10 6
TABLE : 10
ANTI HIV & ANTI CANCER ACTIVITY OF SOME 1-(2-HYDROXY BENZOYL AMINO)-4-ARYL-3-CHLORO-2-0XO AZETIDINES ------------------------------------------------------ ----------------------------------------------~------- --------------
No. AI Anti HIV activity Anti cancer activity Infectea- t.minfe. Dose Responce Res. molar
%growttltypeoI cancer
Cell GI SO TGI lIne
LC50 ----------------------------------------------------------------.---------------------------------------------------------(1) (Z) (3) (4) (5) (6) (7) (8) (9) (0) (11 ) --------------------------------------------------------------------------------------------------------------------------
1. 2-0H-C6H4 7.73 106.87 Not Noteworthy
2. 4-0Cli3-C6H4 8.34 97.87 Not Noteworthy
3. 4-NOZ-C6H4 9.41 79.32 Not Noteworthy
4. 3-NOZ-C6H4 10.37 84.89 Not Noteworthy
5. 2-Cl-C6H4 11.09 106.48 Not Noteworthy
6. 3-CI-C6H4 9.86 86.35 Not Noteworthy
7. 4-0H-C6H4 9.51 84.78 100 C IMS-273 1. 29xI 0 -5 Z.5Sx10- S S.OSx10 -S
100 E U-2SI 1. 43x10 -5 Z.73x10- 5 5.23xlO -5
100 F SKMEL-5 1. 46x10 -S Z.77xlO- 5 5.26x10- 5
100 H UO-31 1. 56xlO- 5 2.90x10- 5 5.39xlO- 5
96 G IGROVI 1. 40x1 0 -5 2.75x10- 5 5.40xlO -5
89 D DLD-1 1. 58x10 -5 3.06x10- 5 -5 S.94x10.
8. 3-0H-C6H4 9.21 89.98 1. SOx10 -6 Not Noteworthy
9. 3-0Cli3-C6H4 10.65 81.84 2.80xlO- 6 Not Noteworthy
10. 3,4-(OCH3)2 10.09 94.42 1. 60x10- 6 Not Noteworthy -C6H4 N
w 0
--------------------------------------------------------------------------------------------------------------.-----------(1) ( 2) (3) (4) (5) (6) (7) (8) (9 ) (10) (11 ) -----------.--------------------------------------------------------------------------------------------------.-----------
11. 3,4,5-(0013 )3
-C6HZ
12. 2-0H-C10H7
8.27 96.48
14.00 83.81
-7 4.60xl0
6.80xl0- 5
Repeat for primary testing
Not Noteworthy
N
'-" ~
232
Table-J.l
ANTIBACTERIAL AND ANTITUBERCUl.AR ACTILVITY OF SOME 1-(4-HYDROXY-6-METHYL PYRIMIDIN-l-YL AMINO)-4-ARYL-3-CHLORO-2-0XO AZITIDINES.
Sr. Ar. No.
(1) (2)
1. -C H 6 5
2. -2-0H-C H 6 4
3. -3-0H-C H 6 4
4. -4-0H-C H 6 4
5 . -4-0CH -C H 3 6 4
6 . -3-NO -C H 2 6 4
7 . -4-NO -C H 1 6 4
8. -2-CL-C H 6 4
OH
~N
~NH-N .. N j
/~ o H
Cl
Ant ibacterial act ivity Ant I.tllbercul ar Zone of inhibition in mm activity
Salmone 11 a Cone. in jJJ.1}/
E.eoli S.aureus typni ml Para A
( 3 ) (4 ) ( 5 ) ( 6 ) (7)
20 18 19 +
18 17 23 +
18 17 17 + +
18 22 17 + +
20 16 16
20 15 18
20 20 17 +
22 15 18 +
(1) (2)
9. -3 -C1-C H 6 4
10. -4-Cl-C H 6 4
11. -3-0CH -4-0H-C H 363
12. -2,4-(OCH ) -C H 3 2 6 3
( 3 )
20
20
21
17
13. -3-0CH -4-0H-5-I-C H 20 3 6 2
14. -CH~CH-C H 6 5
15. -C H 0 6 3
16. -2-0H-5-Br-C H 6 3
17
17
17
17. -2-0H-3,5-(br) -C H 16 262
18. -4-N(CH ) -C H 12 3 2 6 4
19. -3,4,5-(OCH ) -C H 14 3 3 6 2
20. -2 -OH-C H 10 6
15
( 4 )
18
15
15
17
20
20
18
12
17
14
16
13
233
( 5 ) ( 6 ) (7)
17 +
17 +
18
20 + +
17 +
18 +
17 +
13 +
16
10
15 +
13 + +
Table lZ
ANTl-HIV & ANTI CANCER ACTIVITY OF SOME 1-(4-HYDROXY-6-METHYL PYRIMIDIN-Z-YL AMINO)-4-PHENYL-3-CHLORO-Z-OXO AZETIDINES -------------------------------------------------------------------------------------------------------------------------No. AI Anti HIV activity Anti cancer activity
% growtl1type of Cell G1 50 line TGI Infected uninfe. Dose
Responce Res. molar LC50 cancer
(1) (Z) (3) (4) (5) (6) (7) (8) (9) (10) (11)
1. 2-0H-C6H4 16.14 20.66 5.90x10 -6 (Repeat for primary testing)
2. 4-0H-C6H4 7.24 90.63 4.Z0x10 -7 100 B NCI-H460 4.10x10 -6 1. 64x10 -5 4.05x10 -5
100 D HCC 2998 1.1Zx10 -5 Z.33x10- 5 4.38x10 -5
100 E SNB-19 1. 07x10 -5 2.25x10 -5 4.75x10 -5
100 H RXF 393 2.85x10 -5 1. Z5x20 -5 3.53x10 -5
98 F UACC 257 1. 24x10 -5 2.51x10 -5 5.08x10-5
98 G OVCAR-3 3.76x10 -6 1. 60x10 -5 4.07x10 -5
3. 3-0H-C6H4 8.16 85.02 9.30x10 -7 Not Noteworthy
4. 4-NOZ-C6H4 11. 50 100.13 5.40x10 -8 100 F M-14 1.10x10 -5 2.30x10 -5 4.80x10 -5
100 H RXF-393 7.60x10 -5 1. 41x10 -5 3.75x10 -5
96 B fl)P-18 1.13x10 -5 2.39x10 -5 5.05x10 -5
91 D HCT-116 9.37x10 -6 2.23x10 -6 5.10x10-6
79 E SF -539 1. 08x10 -5 2.70xlO -5 6.76x10 -5
N
'" ... Contd ...
-------------------------------------------------------------------------------------------------------------------------(1) ( 2) (3) (4) (5) (6) (7) (8) (9 ) (0) (11 ) -------------------------------------------------------------------------------------------------------------------------
5. 3-N02-C6H4 13.47 62.38 1. 70xlO -5 95 B NCIH 226 1. 93xlO- 5 3.41xlO -5 6.02xlO- 5
91 F M-14 1. 73xlO-p5 3.22xlO- S 6.01xlO- 5
79 D Her-IS 1. 51xlO- 5 3.15xlO- 5 6.57xlO -5
67 H SN-12C 1. 81xlO- 5 3.76xlO- 5 7.82x10 -5
50 A HL-60 (TB) 1. 35xlO- 5 3. 68x1 0- 5 1. OOxlO -4
6. 4-Cl-C6H4 8.38 100.74 1. 80x10 -8 100 E SNB-19 1. 61x10 -5 2.96xlO- 5 5.44x10 -5
100 H RXF-393 1. 22x10- 5 2.46xlO -5 4.96x10 -5
98 D Her-1l6 1.38xlO- 5 2.70x10 -5 5.28xlO -5
96 F SJa-IEL- 5 1. 41x1 0 -5 2.77x10 -5 5.41x10 -5
91 B Ncr - H322 1. 66x1 0 -5 3.15x10- 5 5.94x10 -5
7. 3-Cl-C6H5 15.62 65.45 2.00x10 -5 86 F SKMEL-5 1. 84x1 0 -5 3.42x10 -5 6.37x10 -5
82 H RXF-393 8.18x10 -5 2.23x10 -5 5.67x10- 5
79 C IMS-273 1. 72x10- 5 3.39x10- 5 6.70x10- 5
56 E SF-539 1. 72x10- 5 3.95xlO -5 9.04x10- 5
52 A MJLT-4 1. 27xlO -5 3.48xlO -5 9.55x10 -5
8. 3,4-(OCH3)2 11.95 103.86 5.90x10-p6 49 A HL60 (TB) 1.39x10- 5 3.76xlO- 5 1. OOxlO -4
-C6H3
Contd ..• N
"" '"
-------------------------------------------------------------------------------------------------------------------------(1) (2) (3) (4 ) (5) (6) (7) (8) (9) (10) (11 ) -------------------------------------------------------------------------------------------------------------------------
9. C4H3O 11.62 79.54 1. 80xl0 -5
56 A
SO A
10. 3,4,5(OCH3)3 11.80 95.53 6.60xl0- 6 94 B
-C6H2 92 F
88 H
84 C
55 E
11. 2-OH-C10H- 14.68 92.32 1.80xl0- 5 97 F
95 H
90 B
79 C
72 D
70 E
RH-II-8226 1.63x10- 5
HL-60 TB 1. 53x10- 5
NCI-H 460 9.35x10- 5
SKMEL-5 1. 28x10 -5
RXF 393 1.23xlO -5
IMS 273 l.04xlO -5
SF 539 1.35x1O-S
M-14 1. 53xl0- 5
RXF 393 1.33x10- 5
NCI H 460 1. 50x10 -5
IMS-273 1.65x10- 5
HCC 2998 1.50X10- 5
SF 539 2.19x10- 5
3.83x10- 5
3.93x10- 5
2.19x10- 5
2.65x1O -5
2.64xlO -5
2.42x1O -5
3.S1x1O -5
2.90x1O -5
2.66xlO -5
2.96x10 -5
1.65x10 -5
3.62x10 -5
4.llxlO -5
9.01xl0- 5
1. 00x10- 4
4.90xl0-pS
S.48xl0- 5
5.65xlO -5
S.6SxlO- 5
9.14xl0 -5
5.50xl0 -5
5.33xlO -5
5.85xlO- 5
6.67xlO- p5
7.09xlO -5
7.74xlO -5
N
"" 0>
237
Tabl e 13
ANTI I.BACTERIAL AND ANTITUBERCULAR ACTIVITY OF SOMF:
,PHENYL ACETYL IIYDRAZINO ARYL ACETONITIIILES
Sr. Ar. No.
(1) (2)
1. -C H 6 5
2 . -2-0H-C H 6 4
3 . -3-0H-C H 6 4
4. -4-0H-C H 6 4
5 . -4-0CH -C H 6 4
6. -3-NO -C H 2 6 4
7. -4-NO -C H 2 6 4
8. -2-Cl-C H 6 4
eN I
(II ill'
Antibacterial activity Ant itubercu1ar Zone of_inhl~.!c!.t0!! in..-'l'!" activity against
SaTmone- H R cone. in e.coli S.aurcus 11a typhi 37 v
Para A fl~ /m1 30 100
( 3 ) (4 ) ( 5 ) ( 6 ) (7)
20 16 17
20 16 17 +
17 14 15 + +
20 17 16 + +
17 15 15
18 17 15 +
20 15 16 +
20 15 17 + +
238
------------------------------------------------------------------(1) (2) ( 3 ) ( 4) ( 5 ) ( 6 ) (7) ------------------------------------------------------------------
9. -3-CI-C H 6 4
10. -3-0CH -4-0H-C H 363
11. -CH=CH-C H 6 5
18
18
17
12. -3-0CH -4-0H-5-I-C H 18 362
13. -2,4-(OCH ) -C H 3 2 6 3
14. -C H 0 4 3
15. -2-0H-5-Br-C H 6 3
17
17
17
16. -2-0H-3,5-(Br) -C H 17 262
17. -4-CH -C H 364
12
18. -3,4,5-(OCH ) -C H 14 3 3 6 2
19. -2-0H-C H 13 10 6
16
15
14
17
22
30
15
20
14
15
12
22
20 +
20
22
18 +
21 + +
20 + +
20 +
13
12 +
15 +
TABLE : 14
ANTI-AIDS & M"TlCA"lCER ACTIVITY OF SCME c:C- PHElIYL AvETYL BrDREZINO ARYL ACE'l'ONITRILE
No. AI Anti HIV acti vi t\" Anti cancer activity Infected uninfe. Dose
molar % growth type of Cell G1 50 TGI
cancer llne Responce Res.
(1) (2) (3)
1. 2-0H-C6H4 7.88
2. 4.NOZ-C6H4 10.69
3. 4-0H-C6H4 16.38
4. 3-0H-C6H4 10.56
S. 3,4-(OCH3)Z- 16.57
C6H3
6. 4-N(CH3)2-C6H4 13.65
7. 3,4,S-(OCH3)3- 11.43
C6HZ
8. 2-0H-1-C10H6 11.13
(4)
84.90
101. 04
35.06
104.38
25.47
95.78
117.20
92.58
(5)
-8 4.10x10
(6)
86
71
(7)
E
C
-8 3.70x10 Not Noteworthy
-4 2.80x10 Not Noteworthy
-6 4.60x10 Not Noteworthy
-4 4.00x10 Not Noteworthy
-5 2.70x10 Not Noteworthy
6.10x10-' Not Noteworthy
-7 5.70x10 67
65
C
E
(8)
ML-4
DMS-114
DMS-1l4
(9)
1.15x10- 5
2.73x10-6
2.08x10- 6
-6 ML-9-MEL-2 2.71x10
(10)
-5 Z.55x10
-6 7.6Zx10
5.38x10- 6
-5 1. 63x1-
LC50
(11 )
-<; 5.67x10 -
-5 4.31x10
-5 3.15x10
-5 6.52x10
N LN <.0
240 Table 15
ANTIBACTERIAL AND ANTITUllf':RCtll.AR ACTIVITY OF SOME ~-(2-HYDROXY BENZOYL HYDRAZINO) ARYL ACEluNITRILES
Antibacterial activity Antitubercular Zone of inhibition in mm activity against
Salmonell H R cone E.coli S.aureus -a typhi __ ~3~7_v~ ______ __
_________________________________________ ~~:~_~ ___ ~~~~~~~_~~~~~l (1) (2) ( 3 ) (4 ) ( 5 ) ( 6 ) (7)
1. -C H 17 2Z 22 + 6 5
2 . -2-0H-C H 18 20 18 + +
6 4
3 . -3-0H-C H 20 18 17 + + 6 4
4. -4-0H-C H 20 19 15 + 6 4
5. -3-NO -C H 19 12 15 + +
2 6 4
6. -4-NO -C H 20 16 15 + + 2 6 4
241
------------------------------------------------------------------
(1) ( 2 ) ( 3 ) ( 4 ) ( 5 ) ( 6 ) (7) ------------------------------------------------------------------
7 . -2-CL-C H 19 13 17 + 6 4
8. -4-CL-C H 22 20 18 + 6 4
9. -4-0CH -c H 23 16 20 3 6 4
10. -2,4-(OCH ) -C H 22 20 17 + + 3 2 6 3
11. -3-0CH -4-0H-C H 18 17 17 3 6 3
12.-3-0CH -4-0H-5-Br-C Ii 18 15 17 3 6 2
13. -2-0H-5-Br-C Ii 18 17 18 + + 6 3
14.-2-0H-3,5-(Br) -C H 18 19 18 + 2 6 2
15. -4-CH -C H 17 15 16 + + 3 6 4
16.-2,4-(OCH ) -6-NO-C H 13 12 15 3 2 2 6 2
17. -4-N(CH ) -C H 12 15 14 3 2 6 4
18. -3,4,S-(OCH ) -C H 14 12 13 + 3 3 6 2
19. -2-0H-C H 0 10 14 12 11 7
M'TI-AIDS & ANTICANCER ACTIVITY OF SCME c(-(2-HYDROXY BENZOYL HYDRAZINO) ARYL ACETONITRILES -----------------------------------------------------------------------------------------------------------------------No. Ar Anti HIV activity
Infected unlnte. DOse Responce Res. molar
(1) (2) (3) (4) (5)
1. C6H5 16.09 109.78 9.04xl0-8
2. 2-OH-C6H4 14.25 84.31 9.20xl0 -7
3. 4-0H-C6H4 16.66 92.14 1.10xl0-6
4. 3-0H-C H 6 4 15.71 108.36 -7 2.00xl0
5. 3-0CH3-4-0H- 15.26 106.81 1. 80xl0
C6H3
6. 3,4-(OCH3 )2- 13.85 66.33 2.50xl0- 5
C6H3
7. 2-OH-I-CI0H6 10.82 96.40 4.10xl0 -7
Anti cancer actintv % growth type of Cell GI 50 TGI LC50 cancer lIne
(6) (7)
49 C
52 C
51 F
Not Noteworthy
45 E
Not Noteworthy
58 B
75 C
69 C
66 B
(8)
DMS-114
DMS-114
ML-4
SF-539
DMS-1l4
NCr -H-23
DMS-114
SKMEL-5
(9) (10) (11)
-7 -6 -4 7.21xl0 4.87xl0 lxl0
2.48xl0-6 7.03xl0- 6 8.56xl0-5
-6 -5 -5 4.44xl0 2.72xl0 9.76xl0
2.93xl0- 5 1.87xl0-5 lxl0- 4
5. 73xl0-'
4.75xl0- 6
1.87xl0-6
2.63xl0-6
-5 1. 27xl0
1. 95xl0 -5
5.14xl0 -6
1.03xl0 -5
-5 7.45xl0
5.79xl0 -5
2.98xl0- o
5.81xl0
N ... N
-5
243
Table 17
ANTIBACTERIAL AND ANTITUBERCULAR ACTIVITY OF SOME oC-(4-HYDROXY-6-METHYL PYRIMIOIN-2-YL HYDRAZINO) ARYL ACETONITRILES
Sr. Ar No.
(1) (2)
1. -C H 6 5
2 . -2-0H-C H 6 4
3. -3-0H-C H 6 4
4. -4-0H-C H 6 4
5 . -3-NO -C H 2 6 4
6. -4-NO -C H 2 6 4
Antiba cterial activity Antitubercular Salmonel- activity against
E.coli S.aureus 1a typhi H R conc Para A 37 v -- - ---'-------
30p.J/ml 100P1/ml
( 3 ) (4 ) ( 5 ) (6 ) (7)
19 12 15
20 12 18 +
17 19 16 +
18 13 15
18 20 15
20 15 15 +
244
------------------------------------------------------------------(1) ( 2 ) ( 3 ) (4 ) ( 5 ) ( 6 ) (7) ------------------------------------------------------------------
7 . -4-0CH -c H 18 13 18 + 3 6 4
8 . -2-CL-C H 19 13 17 + + 6 4
9. -3-CL-C H 18 13 15 6 4
10. -4-CL-C H 22 13 16 + 6 4
1I. -3-0CH -4-0H-C H 18 17 15 + + 3 6 3
12. -2,4-(OCH ) -C H 19 13 16 + 3 2 6 3
13. -3-0CH -4-0H-5-I-C 11 17 12 15 + + 3 6 2
14. -CH~CH-C H 17 16 15 + 6 5
15. -C H 0 18 14 15 +
4 3
16. -2-0H-5-Br-C H 14 15 15 6 3
17. -2-0H-3,5-(Br) -C H 15 12 10 2 6 2
18. -4-N(CH ) -C H 10 13 14 3 2 6 4
19. -3,4,5-(OCH ) -C H 13 10 12 + 3 3 6 2
20. -2-0H-C H 12 15 14 10 6
TABLE: 18
ANTI AIDS & ANTICANCER ACTIVITY OF SCME c(-(4-HYDROXY-6-MEIHYL PYRIMIDIN-Z-YL HYDRAZINO) ARYL ACETONITRlLES --------------------------------------------------------------------------------------------------------------------------No. AT Anti HIV activity Anti cancer activity
Infected uninfe. Dose Responce Res. molar
% growth type of cell GI SO TGI LCSO cancer lme --------------------------------------------------------------------------------------------------------------------------(1) (2 ) (3) (4 ) (5)
1- Z-OH.C6H4 10.Z7 104.49 S.90x10
Z. 4-0H-C6H4 24.13 116.46 1. 80x10
3. 3-0H-C6H4 9.41 101.15 3.S0x10
4. 4-N01-C6H4 9.04 105.91 2.00xlO
s. 3-N01-C6H4 9.19 106.80 1. 40x10
6. 3,4-(OCH3)Z- 24.38 48.18 7.90x10
7. 2-C4H3O 11.80 93.45 3.90x10
8. 4-N-N-(CH3)Z- 12,6Z 99.39 6.31x10
N-C6H4
9. 3,4,5-(OCH3)3 10.68 105.13 3.33x10
-C ~ 6 •
10. Z-OH-1-C10H6 11.80 85.30 S.20x10
(6) (7)
-8 Not Noteworthy
-4 Not Noteworthy
-6 Not Noteworthy
-7 Not Noteworthy
-8 Not Noteworthy
-4 Not Noteworthy
-6 Not Noteworthy
-7 Not Noteworthy
-6 Not Noteworthy
-7 100 D
95 F
(8) (9)
KM-Z 4.29x10-6
UACC-62 2.87)(10-6
(10)
1. 73)(10- 5
1. Olx10- S
(11 )
4.16x10- S
3.37x10- S
N
""" '"
National Cancer Institute Developmental Therapeutics Program In-Vitro Screening Data Review Checklist
;C: 653R47-M/O-I/26 Experimenl ID: 9211 NSR4 I Source:
.1 nute: Novem ber 9, 1992 Review Dale: January 15, 1993
Pending Action hy the NCt for this experiment
I. None 2. X Repeat testing in the Primary Screen 3. Refer to Biological Evaluation Committee 4. Currently under Review by Biological Evaluation Committee
Comments
NSC 653847 0 • "- /~ 0 " •
It It I
" C N " " ~"- / "- / "- / "- ~"-" " N C " " I It I I II
" " C • " ~/ "- III ~ /
" 0 N "
•
National Cancer Institute Developmental Therapeutics Program Tn-V~tro Testing Results
653R47 -M / 0-1 /26 E.""riment ID: 9211NS84 Test Type: 8 Units: Molar
ort Date: Jarmary 15, 1993 Test Date: November 9, 1992 QNS: MC:
II: Stain Reagent: Dual-Pass SSPL: OCBU
L0910 Concentration rime Hean Optical o.ruilit1 •• Percent Growth
&l/C", 11 Line Zero Ctrl -8.0 -1.0 -6.0 -5.0 -4.0 -8.0 -7.0 -6.0 -5.0 -4.0 corso TGI LC50 10;<"".:.,,, ::O.F-CEM 0.267 1. 287 1. 308 1.183 0,682 0.410 0.282 102 90 39 12 -2 6.16E-07 7.S2E-OS >1. OOE-Ot flL-60 (TEl) 0.246 0.935 0.949 0.954 0.411 0.204 0.1"13 102 103 2' -18 -30 4.66E-07 3.74E-D6 >1.00£-04 1(- 562 0.221 1. 411 1.329 1. 410 1. 235 0.382 D.le? " 100 B5 14 -I' 3.l0E-06 2.9lE-OS >1.00E-04 "I0LT-4 0.4.51 1.776 1.823 1. 781 1.271 0,645 0.389 104 100 .2 15 -14 1. 79E-06 3.26E-05 >1.00£-04 Fi.PHI-e226 0.4.31 1.663 1. e99 1.898 1.569 0.753 0.419 103 102 '0 22 -3 3.29£-06 7.636;-05 >1.00£-04 SR 0.;':85 D.971 O.9~6 0.928 0.466 0.329 0.213 98 " 26 6 -. 4.46E:-07 4.11£-05 >1.00£-04 ~Sm!lll Cell Lung C!ln04lr '549/ATCC 0.350 1. 569 1. 521 1. 503 1.422 0.441 0.299 .6 .5 88 7 -14 2.96£-06 2.19£-05 >1.00£-04 E.KVX ~OP-lE' 0.610 0.929 0.927 0.903 0.851 0.567 0.504 •• .2 76 -7 -17 2.04£-06 8.20£-06 >1.00£-04 ~OP-62 1. 051 1.747 1. 757 1. 674 1.571 1.025 0.714 102 •• 74 -3 -32 2.07£-06 9.13£-06 >1.00£-04 ~OP-~2 0.626 0.IH7 0.924 0.933 0.863 0.709 0.446 .3 •• 74 2' -2' 3.14£-06 2.97&:-05 >1.00£-04 ~C!-H226 0.701 0.965 1.060 1. 074 1.007 0.626 0.562 13' 141 116 -11 -20 3.31£-06 8.23£-06 >1.00£-04 ~CI-H2 3 0.476 1.382 1.346 1.343 1.271 0.748 0.179 •• •• " 30 -63 4.50£-06 2.11£-05 1.29£-05 KI-H322M 0.636 1.600 1. 558 1. 500 1.351 0.951 0.656 .6 '0 75 23 2 3.00£-06 >1.00£-04 >1.00£-04 ~CI-H460 0.254 1.182 1. 924 1.152 1.553 0.493 0.307 103 •• " 15 3 3.16£-06 >1.00£-04 >1.00£-04 ~Cl-li5n 0.451 1.161 1.154 1.121 1.023 0.720 0.247 •• •• .0 37 -46 5.09£-06 2.81£-05 >1.00E-04 ex," ". 0.289 1.150 1.154 1.141 0.982 0.525 0.211 100 99 Bl 27 -25 3.76£-06 3.34£-05 >1.00£-04
" C.ll Lung C.nc.r >.s 114 0.6t16 1.116 1.714 1.643 1. 519 0.461 0.213 100 93 Bl -33 -.. 1.87£-06 5.14£-06 2.98£-05 ,.s 273 0.12"1 0.898 0.933 0.981 0.737 0.171 0.078 10' •• " • -36 2.52£-06 1.42£-05 >1.00£-04 )n C.ncer :01.0 ," 0.ll8 1.290 1.200 1.222 1.165 0.966 0.192 91 93 " 67 -40 1.43£-05 4.24£-05 >1.00£-04 )LLl-l 0.241. 1.365 1.294 1.304 0.939 0.~08 0.381 .. 95 62 2. 13 2.06£-06 >1.00£-04 >1.00£-04 KC-2!'96 -!CT-l1!> 0.250 2.268 2.241 2.364 1.890 0.737 0.156 99 105 Bl " -37 3.52£-06 2.47£-05 >1.00£-04 KT-15 0.375 1. 925 1.923 1. 945 1.620 0.539 0.542 100 101 SO 11 11 2.12&-06 >1.00£-04 >1.00£-04 iT29 0.291 1. 729 1. 723 1.625 1.639 1.349 0.317 100 93 " 74 2 2.13£-05 >1.00E-04 >1.00E-04 <M12 0.325 1.663 1.609 1. 666 1.552 0.604 0.423 96 102 .2 21 7 3.87£-06 >1.00E-04 >1.00£-04 (M20L2 0.368 1. 455 1.437 1.411 1. 423 1.148 0.315 9B .. 97 72 -14 1. 79E-05 6.60E-05 >1.00£-04 ;w-620 0.167 1.162 1.145 1.131 0.977 0.511 0.368 " 97 61 35 20 4.67£-06 >1.00E-04 >1.00£-04 CanceI" ;F-:l68 0.541 1.866 1.964 1.611 1. 419 0.842 0.419 100 " 66 23 -23 2.36£-06 3.18E-05 >1.00£-04 ... -295 0.275 1.241 1.191 1.243 1.159 0.338 0.:269 " 100 92 6 -2 3.06E-06 5.6OE-05 >1.00£-04 ;f-539 0.513 1.624 1.758 2.266 1.123 0.643 0.385 112 160 109 12 -25 4.04£-06 2.08£-05 >1.00£-04 ;tai A19 ;N&-'l5 0.552 0.938 0.910:, 0.903 0.667 0.105 0.472 " 91 .2 39 -14 5.63£-06 5.39E-05 >1. 00£-04 ;Nf>-7b U. 470 1. 5:24 1.607 1. 439 1. 366 1.138 0.661 10. 92 " 63 18 1.98E-05 >1.00£-04 >1. 00£-04 1251 0.414 1.357 1. 385 1.356 1.104 0.545 0.300 103 100 73 14 -2. 2.46£-06 2.16£-05 >1. 00£-04
" ". ,nom.ll .ox IONI 0.229 1.248 1.203 1.175 0.921 0.262 0.187 96 93 6B 3 -18 1.89£-06 1.41£-05 >1.00£-04 IALHE-3M 0.561 1. 369 1.402 1. 345 1.320 0.805 0.292 10. 97 .. 30 -48 4.89£-06 2.43£-05 >1.00£-04 n. 0.269 0.939 0.922 0.906 0.183 0.255 0.192 97 " 77 -5 -2' 2.12£-06 8.64£-06 >1. 00£-04 U9-MEL 0.260 1. 054 1.048 1. 044 0.792 0.251 0.162 99 99 67 -1 -30 1.78E-06 9,62£-06 >1.00£-04 ,},;-MEl-2 0.517 0.887 0.875 0.776 0.775 0.648 0.446 97 70 70 35 -14 3.77£-06 5.26E-05 >1.00£-04 ,}';-HEL-28 0.317 1.044 1.076 1.026 0.900 0.641 0.431 10. 9. SO .. " 7.01£-06 >1,00£-04 >1.00£-04 ,K-HEL-5 0.331 1. 290 1.251 1.263 1.150 0.340 0.114 9. 97 " 1 -66 2.63£-06 1. 03£-05 5.81E-05 IACC-257 0.544 1. 362 1. 388 1. 2 80 1.298 0.126 0.425 101 " 59 22 -22 3.18£-06 3.14£-05 >1.00£-04 Ihee-ti2 0.448 1.303 1.334 1. 348 1.116 0.386 0.214 10. 105 " -14 -52 2.26£-06 1.23£-06 8.14£-05 ) aI, Can~er GF((JVl 0.221 0.873 0.850 0.827 0.140 0.3 B 9 0.117 97 " .0 2' -20 3.55£-06 3.66£-05 >1.00£-04 Jl/CAR-3 0,461 1.199 1.194 1.142 0.942 0.538 0.221 99 .2 65 10 -52 1.89E-06 1.47£-05 9.27£-05 IVCAR-4 0.362 0.916 0.905 0.782 0.740 0.553 0.340 " 7' •• " -. 3.46£-06 1.03£-05 >1.00£-04 "ICAR-5 0.456 0.735 0.130 0.663 0.121 0.599 0.333 9B 74 " 51 -27 1.04£-05 4.53£-05 >1.00£-04 Jl/CAft-8 0.233 0.992 0.964 0.982 0.122 0.34.6 0.109 •• 99 " 15 -53 1.95£,-06 1.65£-05 8.91£-05 fii,-OV-J 0.5116 1.195 1.121 1. 048 1.109 0.154 0.517 " 7' 86 2. -12 4.13£-06 5.02£-05 >1.00£-04 1 Cancer 86-0 0.199 0.998 0.982 0.965 0.641 0.270 0.181 ". " •• " • -. 1.34£-06 3.08£-05 >].00£-04
CHN 0.614 1.B03 1. 799 1.766 1. 576 0.612 0.485 100 97 Bl 0 -21 2.40£-06 9.89E-06 >1.00£-04 MI-l 0.661 1.106 1.0U 1.153 1.248 0.627 0.424 96 110 132 -, -3' 3.96£-06 9.18£-06 >1.00£-04 XF-393 0.476 0.937 0.915 0.911 0.811 0.653 0.533 95 .. 74 3B 12 4.72£-06 >1.00£-04 >1.00[.-04 XF-631 N12e 0.351 1.056 1.115 1.135 0.913 0.621 0.218 10, III '0 39 -38 5.39£-06 3.22£-05 >1.00£-04 K-I0 0.839 1. 388 1.421 1. 395 1.395 0.961 0.661 10. 101 101 22 -21 4.46£-06 3.27£-05 >1.00£-04 0-31 0.876 1.704 1.660 1.649 1.533 0.182 0.613 95 93 79 -11 -30 2.12£-06 1.60£-06 >1.00E-04
•
---- ------------------------
National Cancer Institute Developmental Therapeutics Program In-Vitro Screening Data Review Checklist
IISC: 653823 -L / 0-1/43 Experiment ID: 92IlNS81 I Source:
rest Date: November 2. 1992 Review Date: January 15. 1993
Pending AClion by the NC! for this experiment
L None 2_ X Repeat testing in the Primary Screen
3_ Refer to Biological Evaluation Commi!!ee 4_ Currently under Review by Biological Evalualion Comminee
Comments
NSC 653823 N 0 III I
*=* 0 C *-* / '- II I ~ ~
* *-C-C-N-N-C-> * ~ ~ '- / * - • III = JIt
National Cancer Institute Developmental Therapeutics Program In-Vitro Testing Results
NSC: 653823 -L / (}-1/43 Experiment ID: 9211NS81 Test Type: 8 Units: Molar
Rep()~ nate: January 20, 1993 Test Date: November 2, 1992 QNS: Me:
COM!: Stain Reagent: Dual-Pass SSPL: OCBU
LOQIO Conc.ntration Ti_ M •• n Optical Dens1 t.i •• Percent Growth
Panel/C.Il Lin. Zero Ctrl -8.0 -7.0 -6.0 -5.0 -4.0 -8.0 -7.0 -6.0 -5.0 -4..0 G150 TO' LC50 L .. Uken,l/il
CCflF-CE'.N 0.383 1. 280 1.331 1. 265 1.065 0,614 0.385 106 " 76 " 0 3.29£-06 >1.00[:-04 >1.00E-04 HL-60 (TB) 0.249 1.187 1.150 1.197 1. 078 0.375 0.238 " 101 as 13 -. 3.25£-06 5.65£-05 >1.00E-04 K-S(,2 0.209 1.111 1.090 1.141 1.176 0.661 D.334 " 103 107 50 14 1.01E-05 >1.00£-04 >1.00£-04 MOLT-4 0.410 1. 408 1.356 1.4.09 1.239 0.617 D.440 95 100 " 21 3 3.38£:-06 >1.00E-04 >1.00E-04 RPHl-8226 0.416 1.556 1. 537 1.479 1.4iO 0.900 0,577 98 9' 92 " 14 7.08E-06 >1.00£-04 >1.00£-04 SR 0.320 1.068 1.152 1.121 1.0&4 0.463 0.292 III 107 102 22 -9 4.46£-06 5.14£-05 >1.00£-04
Non-Small Cell lUnI;! CanCflr A549/ATCC 0.304 1.196 1.186 1.214 1.170 0.776 0.351 99 102 97 53 5 1.15£-05 >1.00£-04 >1.00£-04 EKVX HOP-18 0.689 0.960 0.990 0.962 0.962 0.8417 0.632 111 101 101 58 -8 1.32£-05 7.49£-05 >1.00£-04 HOP -62 0.437 1. 091 1.000 0.974 0.906 0.592 0.351 " 82 72 ,. -20 2.84E-06 3.S3E-OS >1.00E-04 HOP-92 0.684 0.908 0.901 0.900 0.905 0.661 0.660 97 9' 99 79 -1 2.32£-05 9.81£-05 >1.00E-04 NCI -H226 0.768 1.129 1.098 1.094 1. 095 1.021 0.660 92 91 91 70 -14 1. 73E-05 6.80E-05 >1.00E-04 NCI-H23 0.464 1.193 1.120 1.On 1.112 0.677 0.526 90 83 89 57 9 1.38E-05 >1. 00E-04 >1. 00£-04 NCI-H322N 0.436 1.000 1.025 1.034 0.933 0.726 0.520 104 106 88 51 15 1.10E-OS >1.00£-04 >1.00£-04 NCI-H460 0.232 1.386 1.391 1.427 1.368 0.722 0.363 100 104 •• ., 11 7.33£-06 >1.00£-04 >1.00E-04 NCI-H522 0.499 1.159 1.171 1.159 1.143 0.761 0.565 102 100 96 " 10 6.641r.-06 >1.00lt-04 >1. 001.-04 !.XFL 529 0.318 1. 237 1.181 1.233 1.162 0.858 0.421 9. 100 92 59 11 1. 53E-05 >1.00£-04 >1.00£-04
SlIIall C.ll L=g Cancer OMS 114 0.695 1.460 1.450 1.449 1. 451 0.603 0.200 99 99 99 -13 -71 2:.73£-06 7.62£-06 4.31E-05 PMS 273 0.193 0.973 0.915 0.921 0.971 0.498 0.224 93 93 100 39 • 6.60£-06 >1.00£-04 >1.00£-04
Colon Cancer COLO 205 0.283 0.933 1.080 1. 070 1.074 0.701 0.472 123 121 122 .. " 2.55E-05 >1.00E-04 >1.00£-04 DLD-l 0.276 1.209 0.934 1.112 1.015 0.870 0.680 71 9' 79 .. 43 4.70£-05 >1.00£-04 >1.00£-04 HCC-2998 HCT-1l6 0.279 1.463 1.414 1. 471 1. 413 0.816 0.417 9' 101 9' 45 12 8.07£-06 >1.00E-04 >1.00£-04 HCT-l5 0.201 1. 278 1.312 1.317 1.134 0.553 0.514 10' 104 87 33 29 4.78£-06 >1.00£-04 >1.00£-04 HT29 0.353 1.451 1.528 1. 541 1.502 0.995 0.330 107 108 105 58 -7 1.35E-05 7.94E-05 >1.00E-04 KM12 0.361 1.604 1.566 1. 633 1. 559 1.065 0.648 97 102 9' 57 23 1.58£-05 >1.00E-04 >1.00£-04 KM20L2 SW-620 O.lB 0.696 0.710 0.728 0.703 0.424 0.331 103 106 101 52 3' 1.42£-05 >1.00£-04 >1.00£-04
CllS (IInc.,r Sf-268 O.~51 1. 386 1.39!l 1.390 1.236 0.948 O. ~47 101 100 82 .. -1 8.!lOri-06 9.62£-05 >1.00£-04 Sf-295 0.266 0.962 0.944 0.975 0.930 0.616 0.350 '7 102 95 50 12 1.02£-05 >1.001t-04 >1.00£-04 51'-539 0.427 1. )75 1.342 1. 385 1.322 0.996 0.422 '7 101 " 60 -1 1.46£-05 9.57£-05 >1.00£-04 SN8-1~
SN&-75 0.541 0.757 0.783 0.776 0.762 0.714 0.471 113 109 103 80 -13 2.10£-05 7.24£-05 >1.00£-04 SNS-78 0.557 1. 066 1. 058 1.102 1.069 1.024 0.769 98 107 101 92 .. 6.05£-05 >1.00£-04 >1.00£-04 U251 0.225 0.999 0.970 0.957 0.808 0.481 0.216 96 95 75 33 -. 3.97£-06 7.80£-05 >1.00£-04 XF .98
Melanoma LOX '><VI 0.177 0.881 0.896 0.997 0.821 0.493 0.161 102 11' 91 " -. 7.76£-06 6.73E-05 >1.00£-04 MALHE-3M 0.486 0.915 0.883 0.932 0.914 0.775 0.460 " 104 100 67 -, 1.74£-05 8.42£-05 >1.00£-04 M14 0.274 0.869 0.863 0.874 0.8,5 0.623 0.040 99 101 .. 59 -66 1.15£-05 2.55E-05 5.67£-05 M19-M£L 0.257 0.708 0.703 0.708 0.678 0.461 0.104 .9 100 9' " -60 7.96£-06 2.70£-05 8.08E-05 SK-MEL-2 0.575 1.000 0.990 1. 003 0.99" 0.996 0.777 98 101 " .9 .. 8.95E-05 >1.00E-04 >1.00£-04 SK-MEL-28 0.391 0.853 0.878 0.882 0.861 0.744 0.465 106 107 102 76 16 2.74£-05 >1. 00£-04 >1.00£-04 SK-Mf.L-5 0.328 1.211 1.215 1.215 1.178 0.622 0.338 100 100 96 5' 1 1.28£-05 >1.00£-04 >1.00£-04 UACC-257 0.505 1. 221 1.258 1.248 1.237 1.043 0.582 105 104 102 75 11 2.46£-05 >1.00£-04 >1.00£-04 UACC-62 0.448 1.093 1.118 1.097 1.046 0.655 0.310 10< 101 93 32 -31 5.05E-06 3.23E-05 >1.00£-04
Ovarlan Canc.r I(oROVl 0.4.33 1.235 1.196 1.217 1.203 0.949 0.555 95 98 96 .. 15 1.96E-05 >1.00E-04 >1.00£-04 OVCAR-3 avCJ.Ji;-4 0.287 0.582 0.620 0.678 0.635 0.469 0.393 113 132 116 62 3' 2.81E-05 >1.00£-04 >1.00£-04 avCAR-5 0.454 0.782 0.787 0.813 0.787 0.694 0.555 101 109 101 73 31 3.50E-05 >1.00£-04 >1.00£-04 (NCAR-a 0.300 1.003 1.025 1.025 0.992 0.713 0.379 103 10' 96 59 11 1.53£-05 >1.00£-04 >1.00£-04 SK-OV-J 0.592 1. 208 1.232 1.252 1. 243 0.945 0.690 10. 107 106 57 16 1.50£-05 >1.00E-04 >1.00£-04
Renal Cancer 786-0 0.269 1. 046 1.042 1.082 0.950 0.568 0.240 A498
9. 105 " " -11 5.82£-06 6.00£-05 >1.00£-04
ACHN 0.623 1.610 1.620 1.645 1.630 0.900 0.498 101 104 102 28 -20 5.05£-06 3.83E-05 >1.00£-04 CARl-1 0.906 1. 4 54 1.370 1.490 1. 386 1.186 0.859 as 107 as 51 -, 1.04£-05 8.09£-05 >1.00£-04 RXF-393 0.591 1.064 1.028 0.966 0.967 0.879 0.767 92 7. 7' 61 37 2.85£-05 >1. 00£-04 >1.00£-04 RX1'-631 SN12C 0.392 1.165 1. HIS 1.154 1.195 0.917 O ... 76 103 " 104 .. 11 2.06&:-05 >1.001:-0" >1.00E-04 T> '0 0.141 1. :I ... 1.lU 1."01 l.U" 1.10' O. PH 111 '" 11' .. " ,. ~OE-o!l >1.001:-0" >1.00E-0" II.' " 0.'"10 I.DO. 1. U11 1.1111 1 ...... 1.01" 0.6111 .. III" " " -" 1 •• 6~-01l ;i."U-OII )l.Otlit-tJ ..
National Cancer Institute Developmental Therapeutics Program In-Vitro Screening Data Review Checklist
" hYIH30·S / 0·1/9 ExperlmenllD: 9211NSH4 I Source:
t Ilale: Novernher 9, 1992 Review Dale: January I), 1993
Pe'.!9ing AClion by the NCI for this experiment
1. None
2. X Repeat testing in the Primary Screen 3. Refer to Biological Evaluation Comrnillee 4. Currently under Review by Biological Evaluation Comminee
Comments
NSC 653830 N 0
National Cancer Institute Developmental Therapeutics Program In-Vitro Testing Results
sc: 6'i3830 -s / 0-1 /9 Experiment lD: 9211NS84 Test Type: 8 Units: Molar
eport Date: January l'i, 1993 Test Date: November 9, 1992 QNS: MC:
OMI: Stain Reagent: Dual-Pass SSPL: OCBU
L0910 Concentrl!lt1on Time Mean Optical 0.0_1t1 •• f'ercent Growth
Par ... l/,:-.. ll line Z.ro Ctrl -8.0 -7.0 -6.G -5.0 -4.0 -6.0 -7.0 -6.0 -S.O -4. 0 G150 TO! LC50 L.uk~ml /'I
CCRf-CEM 0.287 1.212 1.198 1.130 0.792 0.459 0.428 " 9I 55 19 15 1. 35E-06 >1. 00E-04 >1.00£-04 HL-oO (TEl 0.248 0,935 0.979 0.661 0.618 0.292 0.287 10. " " • • 1.20£-06 >1.00E-04 >1. OOE-04 1\- 562 D.221 1.353 1. 373 1. 395 1.340 0,391 0.34] 102 104 " 15 11 3.82E-:06 >1.00E-04 >1.00£-04 M('LT-4 0.451 1.691 1.691 1.664 1.205 0.628 0.673 100 " 61 14 18 1.71£-06 >1.00£-04 >1,00£-04 I<I'MI -ILI,t6 0.4)1 1.762 1.73011 1.157 1 • ~2 ~ O. He 0.559 PI 100 " " 10 3,861:-06 >1.00[-04 >1,001-04
" O • .!8!> 0.989 1.001 0.941 0.618 0.289 0.2403 102 " 4? 0 -l5 8.701:-07 1.081:-0:'.1 >1.001:-04 Non-!;m,,11 C.ll l.ung Cone.I"
A~49.'ArCC 0.) 50 1. 599 1.618 1.612 1.538 0.769 0.294 102 101 95 34 -16 5.40£-06 4.15£-05 >1.0011:-04 EKVX HOP-IS 0.610 0.972 1.061 1. 006 0.953 0.700 0.U6 124 1!J9 " " -20 4.361:-06 3.54E-O!l >1.001-04 H,·l'·C./ 1. O!>i 1. a~n 1.9H 1.960 1. 940 1. !II i 1.191 III 114 111 " 17 1.!>61-0!l >1.00E-04 >1.00l-04 It, ,1 - 'IJ 0.626 O. ill!> 0.924 0.900 0.144 O. iO] 0.4!>7 101 " ." 2? -;0 3.34'1:-06 ].14l-0!l >1.001:-04 N,-I ·Il.'le 0.101 1. 036 1. 080 1. 041 1.166 0.916 0.4.24 113 101 '" 82 -40 1.84t-O!l 4. BE-a!! >1.00E.-04 NCl 11.0 0.476 1. 415 1. 480 1. 444 1. 370 0.811 0.447 100 " 89 39 -. 6.161:-06 7.35£-05 >1.00E.-04 NCI-H322M 0.636 1.359 1. 331 1. 388 1.258 0.843 0.609 97 104 86 29 -, 4.23£-06 7.42E-05 >1.00£-04 NCI-H460 0.254 1.846 1.85S 1.!H6 1.758 0.679 0.328 101 104 95 27 5 4.53£-06 >1.00E-04 >1.00£-04 IIlCI-II~22 0.457 1.181 1.153 1.171 1.043 0.7U 0.449 "
., 81 36 -2 4.5121:-06 8, Si'41.-05 >1.001:-0<11 LXFL 529
Small (:.11 l.w-'9 Cone.I" DMS 114 0.686 1.6.0 1.662 1.581 1. 535 0.462 0.223 102 93 '9 -33 -,7 2.081:-06 5.38£-06 3.15£-05 DMS 273 0.121 0.129 0.817 0.760 0.671 0.236 0.063 115 lOS 91 19 -48 3.681:-06 1. 91£-05 >1.00£-04
Colon Cone.I" Ce,l.O 205 0.318 1. 318 1. 373 1.322 1. 352 1.291 0.326 106 100 lOJ 97 1 3.10E-05 >1.00£-04 >1.00£-04 DLD-l 0.242 1. HO 1.366 1.270 1.129 0.55!i O. lSIl 103 " " " 14 3.96t-06 >l.OOt-Ot >1.00E-04 HCC-1998 Her-llti 0.250 1. 932 1.906 1. 872 1.695 0.734 0.248 98 96 " 29 -1 4.25£-06 9.26i.-OS >1.00£-04 Her-IS 0.375 2.242 2.091 2.122 1. 756 0.113 0.637 92 94 7' 18 14 2.68£-06 >1.00£-04 >1.00E-04 HT29 0.291 1.568 1.549 1.562 1.!i32 1.101 0.264 99 100 07 63 -9 1. 53£-05 7,42£-05 >1.00£-04 KM12 O. )25 1.72:'.1 1.75 S 1.6651 1 .657 0.H2 0.447 102 " " J3 , 5.37£-06 >1.001.-04 >1.001;-04 !\H/"I.) O. HI' 1.5H 1. :'.1&1 1. us 1 .... 1.:2lP ().:205 101 " " " -44 1.5n.-O:'.l 4.201:-0:'.1 >1.0(!1:-04 .w ~ ... " D. III 1.1U 1. '00 1.1'0 1.0111 0.1111' II. HII' lUI " '" " " !I.'9L-O. >1.nuJ:-04 >1.0£lL-U<I
N' . ~", ., ., , "" U. HI 1.<1.111 1. <II:! 1.1el 1. U·/I O.IU'.l \I."~!:' '"' " 0' "
. I f. I • ' .... ·011 J. JUI:-UD -'1. hUI. , .. .. • 11', 0.21:'.1 1.ltl 1.215 1.1"'16 1.170 0.1111 O.lll 1", .. .. " , •. Ufll,-{J6 >I.0ut-04 :.-1 .OUI.-I," .,
'" O. :'.Ill 1.700 1.546 1.442 1.411 0.801 0.472 ,7 " 7. " -. 1.15£-06 :'.1.62.1:-05 >1.00.1:-04 SN.,-19 StlB-75 0.552 0.803 0.828 0.1514 0.797 0.661 0.424 110 104 .7 43 -23 7.55£-06 4.49£-05 >1.00£-04 SNB-78 0.470 1. 258 1.186 1.151 1.108 0.938 0.424 91 ,. " 59 -10 1.36£-05 7.20£-05 >1. 00E-04 U251 0.414 1.506 1.H6 1. .78 1.301 0.637 0.326 99 97 " 20 -21 3.29£-06 3.09£-05 >1.00£-04 XF .. ,
~lonoma
LOX IM\~ 0.229 1. 526 1.530 1. 4 69 1.109 0.480 0.202 100 96 " 19 -12 2.33£-06 4.18£-05 >1.00£-04 MALHE-3M 0.561 1.091 1. 089 1.084 1.061 0.125 0.433 100 98 94 31 -23 5.00£-06 3.77£-05 >1.00E-04 M14 MI9-MEt 0.260 0.948 0.950 0.934 0.175 0.381 0.090 100 96 75 18 -65 2.71£-06 1.63£-05 6.52£-05 StI:-HEL-2 0.517 0.986 1.001 0.991 0.936 0.622 0.428 104 101 89 22 -17 3.87£.-06 3.68E-05 >1.00£-04 SK-M.EL-28 0.317 0.873 0.816 0.859 0.103 0.542 0.317 100 97 •• 40 4.67£-06 >1.00E-04 >1.00£-04 SK-HEl.-5 0.331 1.337 1.280 1.304 1.154 0.448 0.132 94 97 " 12 -'0 2.84£-06 1.45£-05 7.23E-05 U1.C(-257 0.544 1. 355 1. 400 1.299 1.377 0.805 0.412 10. 93 lOJ 32 -24 5.56£-06 3.11£-05 >1. 00i;-04 U1.CC-62 0.448 1.332 1. 355 1.2851 1.259 0.517 0.213 103 95 92 e -52 3.14£-06 1.34£-05 9.10£-05
;No[Cllln Cooc.:r IGRO'Jl 0.221 0.864 0.873 0.845 0.750 0.443 0.234 101 97 " 34 2 4.74£-06 >1.00E-04 >1.00£-04 avCAJ<.-3 0.461 1. 300 1. 323 1.281 1.171 0.573 0.474 103 98 " 13 1 3.lOE-06 >1.00E-04 >1.00£-04 avCAR-4 0.362 0.954 0.953 0.952 0.937 0.687 0.420 100 100 97 55 10 1.28£-05 >1.00£-04 >1.00£-04 C1VCAJ. - 5 0.456 0.843 0.809 0.851 0.852 0.762 0.470 91 102 102 79 • 2.43£-05 >1.00E-04- >1.00£-04 OVCAJ<.-b O.LH 0.976 0.955 0.984 0.899 0.431 0.273 97 101 90 27 5 4.25£-06 >1.00£-04 >1.00£-0<11 SK-('/\'-3 0.586 1.221 1. 221 1.259 1.256 0.784 0.478 100 106 106 31 -18 5.59£-06 4.25£-05 >1.00E-04
~.nol Cftne"'I" 71:16-0 0.199 0.968 1.004 0.937 0.786 0.424 0.140 105 96 7. 29 -29 3.63E-06 3.15£-05 >1.00E-04 A498 ACHN 0.614- 1.831 1.824 1. 815 1.713 0.732 0.540 99 '9 90 10 -12 3.16£-06 2.18£-05 >1. 00E-04 CAKl-1 0.661 1.298 1.436 1.433 1.292 0.720 ,0.315 122 121 .9 9 -52 3.52£-06 1.41£-05 9.14£-05 RXf-393 0.476 0.889 0.898 0,818 0.846 0.674 0.426 102 98 90 " -10 9.01£-06 6.64£-05 >1. 00£-04 RXf-631 SN12C 0.351 1.102 1. 075 1. 055 0.990 0.618 0.216 96 9' " 35 -21 5.09E-06 4.21£-05 >1.00£-04 TtI:-I0 ,).838 1. 559 1. 516 1.681 1.605 1.353 0.923 102 117 10. 71 12 2.29E-05 >1.00£-04 >1.00£-04 UO-31 0.876 1.677 1.690 1.746 1.606 0.790 0,587 102 109 91 -10 -13 2.56£-06 8.00E-06 >1.00£-04
National Cancer Institute Developmental Therapeutics Program In-Vitro Screening Data Review Checklist
c: 654820 -T / 0-1 / I7 Experiment 10: 9211SC22 I Source:
t Date: November 16, 1992 Review Date: February 5,1993
Pending Action by the NCI for this experiment
I. None
2. X Repeat testing in the Primary Screen
3. Refer to Biological Evaluation CommiUee
4. Currently under Review by Biological Evaluation Commillee
Comments
USC 654820
Cl •
" l' " • • I II
N-- N 1/ II
* * * C N ~ ~ " / " / " / " / " / ~ • • 0 S C • •
I II II II I
* * * * 0 "/( * c ~/" /~/ ,,~,,/
• C= N • * 0
-----------------------------------------
National Cancer Institute Developmental Therapeutics Program In-Vitro Testing Results
;C: 654820 -T / 0-1 / 17 Experiment ID: 9211SC22 Test Type: S Unit.: Molar
,port Date: February 10, 1993 Test Date: November 16, 1992 QNS: MC:
)MI: Stain Reagent: Dual-Pass SSPL: OCBU
LOQIO Concentration Ti_ H •• n Optical Den_iti •• Percent <;rowth
'anal/Cell Line Zero Ctrl -8.0 -7.0 -6.0 -5.0 -4.0 -8.0 -7.0 -6.0 -5.0 -4.0 COI50 TG! LeSO .euk .. lrLlll
CCf<.F-CE:M 0.314 1.245 1.188 1.235 1.088 0.487 0.303 •• ., 83 19 -. 3.26£-06 6.84£-05 >1. ODE-Doll HL -00 (TB) 0.486 1.982 1.844 1.913 1.586 0.704 0.369 91 " " 15 -24 2.51£-06 :2.38£-05 >1.00£-04 f(-~62 0.204 1.402 1.365 1.322 1.262 0.566 0.216 97 " as 30 1 ".:i"1E-C6 )1. ODE-Doll >1.00£-04 MVLT-4 0.339 1.31"1 1. 412 1. 355 1.263 0.928 0.254 103 " .. 57 -25 1.21E-05 4.92£-05 >1.00£-04 RPMl-8226 0.379 1.157 1.156 1.136 1.081 0.690 0.345 100 97 90 40 -. 6.30£-06 6,52£-05 >1.00£-04 SR 0.305 1.649 1.607 1.600 1.530 1.104 0.256 97 96 91 " -16 1.)3E-05 6.13E-05 >1.00E-04
lon-Small Cell Lung Cancer A549/ATCC 0.374 1.565 1. 576 loS):; 1. 518 1.494 1.192 101 '7 96 •• 6. >1.00£-04 >1.00E-04 >1.00£-04 EKVX 1.041 1.8'9 1.829 1.763 l.7oS 1.698 1.202 " .. " 78 '6 3.S1E-OS >1.00E-04 >1.00K-04 H0I'-16 0.490 1.026 1.013 1.055 0.969 0.794 0.435 '7 105 ,. " -11 1.25E-05 6.81£-05 >1.00E-04 HOI' -61 0.233 0.780 0.729 0.7l0 0.731 0.541 0.218 91 '7 ., 56 -7 1.26i.-05 7.84i:-05 >1.00£-04 H0i'··9:.: NCI-H2l6 0.836 1.515 1.450 1. 455 1.432 1. 392 0.628 .0 91 " " -25 l. 99E-05 5.83E-05 >1. 00E-04 NC!-H21 0.578 1.449 1.507 1. 4 83 1. 457 1.315 0.546 107 10. 101 85 -5 2.43£-05 8.74E-05 >1.00E-04 Ncr -HJ 22M NCI-ti4ciO 0.352 1. S03 1.901 1.837 1.817 1. 741 0.774 103 .. '7 92 " 4.52£-05 >1.00£-04 >1.00£-04 t"-!-fj~,:~ 0.643 1.147 1.133 1.121 1.116 1.067 0.635 97 95 94 " -1 2.67£-05 9.67£-05 >1.00£-04 LXFI. 5.'9 0.309 1.436 1.429 1.411 1.367 1.014 0.366 " ., 94 63 5 1. 65E-05 >1. 00E-04 >1.00E-04
;1\",41 11 ,-:"11 Lung Ce.ncer OMS 114 0.313 0.941 0.937 0.910 0.914 0.707 0.292 .. 95 '6 63 -7 1.53£-05 6.01£-05 >1.00E-04 e'MS 213 0.200 0.954 1.031 1.018 1. 035 0.919 0.179 110 10' III 95 -10 2.66E-05 7.96E-05 >1.00E-04
:0100 Cllnc~r COLO 205 0.256 1.272 1.245 1.293 1.224 1.198 0.131 '7 102 95 93 -49 2.00£-05 4.49£-05 >1.00E-04 OLu-1 O.I.l44 0.157 0.160 0.156 0.083 0.028 HCC-2998 0.081 0.194 0.177 0.194 0.141 0.004 HeT-116 0.328 1.772 1.720 1. 757 1.617 0.900 0.124 • 6 .. .. .0 -62 6.17£-06 2.45E-05 7.59£-05 HeT-15 0.372 1. 654 1.764 1.673 1.523 0.772 0.238 10' 101 .0 31 -36 4.77£-06 2.91E-05 >1.00£-04 HT29 0.297 1.541 1.668 1.625 1. 537 1. 738 0.335 110 107 100 116 3 3.83E-05 >1.00E-04 >1.00£-04 KM12 0.648 2.144 1.995 2.093 2.016 1.688 0.546 .0 ,7 91 70 -1' 1.69E-05 6.54E-05 >1.00£-04 KM20L2 0.362 1. 576 1.561 1. 527 1. 573 1.550 0.579 .. .6 100 " 18 3.97£-05 >1. 00E-04 >1.00£-04 51+- 620 0.181 l. 010 1. 051 1.096 1.008 0.646 0.266 105 110 100 56 10 1.36£-05 >1.00E-04 >1. 00£-04
:NS Cancer SF-268 0.433 1.182 1.128 1.135 1.066 0.741 0.325 93 94 " 41 -25 6.23E-06 4.19£-05 >1.00£-04 5f-295 0.746 2.202 2.105 2.215 2.109 2.049 1.291 93 101 94 .0 37 5.73£-05 >1.00E-04 >1.00E-04 Sf-S39 SNB-19 0.303 1. 306 1. 222 1.267 1.238 0.97l 0.430 .2 .6 93 67 13 2.03E-05 >1.00E-04 >1.00E-04 SNB-75 0.314 0.667 0.651 0.664 0.642 0.622 0.329 94 .. 91 as -l2 2.28E-05 7.5lE-OS >1.00£-04 SNB-7& 0.569 0.944 0.906 0.938 0.953 0.908 0.505 '0 .. 102 .0 -11 2.49£-05 ;.73£-05 >1.00£-04 U251 0.434 1.902 1.911 1. 856 1. 823 1.355 0.589 101 '7 95 63 11 1.76E-05 >1.00£-04 >1.00E-04 XF ." 0.454 1. 057 1.064 1.072 1.066 0.886 0.358 101 103 102 72 -21 1. 71t-05 5.92£-05 >1.00E-04
.. lllnoma LOX IMVl 0.235 0.875 0.929 0.891 0.847 0.523 0.131 10. 103 .6 45 -44 7.98E-06 3.19£-05 >1.00E-04 MALM£-3M 0.496 1.026 1. 051 1.117 1.119 1.069 0.619 105 117 117 10' 23 4.83£-05 >1.00£-04 >1.00£-04 "'. 0.366 1. 333 1.350 1.311 1.369 1.107 0.356 102 .. 104 77 -3 2.17£-05 9.27E-05 >1.00E-04 MI9-MEL 0.291 1.178 1.140 1.201 ].128 0.654 0.254 .6 103 " 6. -13 1.50£-05 6.81£-05 >1.00£-04 SK-MEL-2 0.400 1.360 1.296 1.310 1.298 1.053 0.261 93 OS 93 6' -35 1.49£-05 4.58£-05 >1.00£-04 Sl(-HEL-28 0.366 0.953 0.970 0.994 0.970 0.787 0.407 103 107 103 71 • 2.04£-05 >1.00E-04 n.00£-04 SK-HEL-5 0.354 1.145 1.616 1.761 1.529 1.366 0.356 ., 101 " 7. 0 2.12£-05 >1.00£-04 >1.00£-04 UACC-257 0.885 2.016 1.791 1.626 1. 772 1.771 0.865 '0 66 7' 7' -2 2.25£-05 9.36£-05 >1.00£-04 UACC-62 0.482 1.42; 1.418 1.396 1.363 1.222 0.567 .. '7 93 7' • 2.56E-OS >1.00£-04 >1.00E-04
:>Varlan Concer IGROVI OVCAR-3 (NCAR-4 0,345 0.886 0.871 0.860 0.868 0.790 0.405 '7 " '7 B2 11 2.84£-05 >1.00£-04 >1. 00E-04 W("Ah-S OVCMI-8 0.341 1.162 1.203 1.145 1.180 1.018 0.40; 105 •• 10' "
, 2.73E-05 >1.00£-04 >l. 00E-04 SK-UV-3 0.475 LOn 1.026 1. 031 1 . 016 1.063 0.570 • 7 .. '6 10' 17 4.16E-05 >1.00E-04 >1.00E-04
It.nal Cancer "/86-0 0.117 0.713 0.700 0.734 0.752 0.666 0.247 A498
.. 10' 107 •• 22 4.15E-05 >1.00E-04 >1.00£-04
AC"HN 0.807 1.637 1.736 1.640 1. 852 1.637 0.695 112 100 l26 100 -14 2.75£-05 7.54£-05 >1.00E-04 CAKI-l RXF-393 0.845 1.286 1. 253 1.239 1.182 1.214 0.998 RXf-631
.3 ,. 76 B4 35 4.84£-OS >1.00£-04 >1.00£-04
SN12C 0.431 1.144 1.153 1.160 1.207 0.922 0.335 101 10' 10' 6' -22 1.61£-05 5.68£-05 >1.00E-04 n;-10 0.661 1.178 1.201 1.174 1.150 1.221 1.098 105 ,. " 10' " >1.00£-04 >1.00E-04 >1.00E-04 U .... -31 0.616 1.621 1.603 1.592 1.495 1.413 0.794 .. '7 .7 7. 18 2.99E-05 >1.00E-04 >1.00£-04
National Cancer Institute Developmental Therapeutics Program In-Vitro Screening Data Review Checklist
sc: 653006 -w I 0-1/31 Experiment!D: 921OSC14 I Source:
~t Date: October 13, 1992 Review Date: January 20, 1993
Pending Action by the NCI for this experiment
I. None
2. X Repeat testing in the Primary Screen
3. Refer to Biological Evaluation Committee
4. Currently under Review by Biological Evaluation Committee
Comments
•
National Cancer Institute Developmental Therapeutics Program In-Vitro Testing Results
IISC: 653006 -w / 0-1/31 Experimenl II): 921OSCI4 Tesl Type: 8 Units: Molar
t.port Dale: January 21.1993 Test Date: October 13. 1992 QNS: MC:
:OMI: Stain Reagent: Dual-Pass SSPL: OCBU
L0910 Concentration T1~ Maan Optical Den.iti •• Percent Growth
Panel/Cell Line tero C«l GI50 TOI LC50 Leukeml a
CCRf-CEM HL-60 (TB) 1(-562 MOLf-4 0.510 1.794 1. '135 1.543 1. 067 0.626 0.551 95 eo 43 9 3 6.62E-07 >1.00E-04 >1. OOE-04 RPMI-8226 0.376 1.16) 1.167 1.002 0.822 0.575 0.313 101 7' 57 25 -17 1.64E-06 .3.99£-05 >1.00£-04 SR 0.321 1. 756 1.586 1. 480 0.964 0.456 0.417 " " " 10 7 7.18E-07 >1,00E-04 >1.00£-04
Non-Small Ctlll Lung Canc.r A549/ATCC 0.398 1. 569 1.600 1.525 1.395 0.783 0.472 103 96 as 33 6 4.69E-06 >1. 00E-04 >1.00£-04 EKVX 0.7'14 1 • .( 04 1.398 1. 408 1.372 0.925 0.712 " 101 95 24 -, 4.30£-06 5.64£-05 >1.00£-04 HOP-IS 0.762 1.056 0.953 1.013 0.950 0.736 0.620 65 " 64 -3 -19 1.60£-06 6.97£-06 >1.00£-04 HOP-a2 o .Hl 0.796 0.756 0.718 0.522 0.374 0.292 93 66 " 25 11 1.14£-06 >1.00£-04 >1.00£-04 HOI--92 0.719 0.990 1.018 1.074 1.008 0.626 0.609 111 131 107 3. -15 6.96£-06 S.2U:-05 >1.00£-04 NC1-H216 1.312 1. 293 1.236 0.693 0.920 0.901 NCI-H23 O. !ill 1.452 1.563 1. 446 1.326 0.646 0.777 112 9' 67 34 27 4.99£-06 >1.00£-04 >1.00£-04 Ncr -1-1322101 0.413 1.131 1.050 1.036 0.910 0.670 0.600 " " " 36 26 3.75E-06 >1.00E-04 >1.00£-04 NCr-H460 0.105 0.836 0.791 0.715 0.373 0.162 0.133 9. 63 36 , • 5.14E-07 >1. OOE-04 >1.00£-04 Ncr -H522 LXFL '" 0.384 1. 632 1. 557 1.513 1.197 0.747 0.344 9. 90 65 29 -10 2.63E-06 5.45E-05 >1.00£-04
Small Cioll LLlflg Cancer [oMS U. 0.400 0.943 0.982 0.930 0.719 0.344 0.271 107 " " -14 -32 1.32£-06 6.44£-06 >1.00E-04 DMS nJ 0.228 1.111 1.124 1.109 0.820 0.304 0.142 101 100 67 • -36 1.96£.-06 1.53£.-05 >1.00£.-04
Colon C"",· .. r COL0 205 0.311 1.262 1.281 1.295 1.297 1.0)1 0.323 102 103 104 76 1 2.21E-05 >1.00E-04 >1.00£-04 DLf.-l 0.073 0.338 0.319 0.236 0.166 0.097 H':C-1996 0.203 0.702 0.667 0.665 0.531 0.386 0.231 93 97 66 37 6 3.46E-06 >1.00£.-04 >1.00£-04 HeT-116 0.421 2.040 2.141 2.066 1.654 0.726 0.462 106 103 76 19 3 2.66£-06 >1.00£-04 >1.00£-04 HCf-15 0.406 1. 943 1.9n6 1.752 1.112 0.709 0.714 " " 46 20 20 7.99£-01 >1.00£-04 >1.00£-04 HT29 0.144 0.793 0.774 0.796 0.795 0.476 0.235 '7 101 100 51 14 1.07£-05 >1.00£-04 >1.00£-04 KM12 0.485 2.099 2.312 2.077 1. 689 0.976 0.635 113 " 75 31 22 3.61£-06 >1.00£-04 >1. 00£-04 KH20L2 0.301 1.146 1.114 1.092 0.996 0.731 0.479 " " 63 51 21 1.07£-05 >1.00£-04 >1.00£-04 SW-620 0.120 1. 095 1. 093 1.072 0.781 0.499 0.378 100 " " 39 26 4.11£-06 >1.00£-04 >1. 00£-04
eNS ":-aneer SF-26b 0.432 1.274 1.311 1.074 0.669 0.664 0.520 104 76 52 2. 10 1.20£.-06 >1.00E-04 >1.00£-04 SF-2~" SF-~39 0.976 1.887 1.795 1.630 1. ?6S 1.145 0.820 90 " 67 18 -16 3.44£-06 3.44£-05 >1.00E-04 SNh -19 0.716 1.434 1.469 1.431 1.306 1.009 0.766 !O, 100 " 41 7 6.0lE-06 >1.001t-04 >1.00£-04 ~Nb- 15 0.619 O. !ill!! 0.956 0.267 0.1110 0.643 0.604 114 " .. , -3 1.81E-06 5.8U:-OS ;>1.00£-04 SNh-7b 0.75) l.H~ 1.368 1. 452 1.301 1.191 0.624 104 118 " 74 12 2.43E-OS >1.00£-04 >1.00£-04 U2 ~.l 0.220 1.041 1.012 0.935 0.763 0.467 0.)01 " 87 66 33 1. 3.03£-06 >1.00\::-04 >1.00E-04 X;. , .. 0.709 0.714 0.703 0.687 0.601 0.479
Mot 1 anoroa L()~: I>!VI 0.371 1. 601 1.558 1.368 0.969 0.453 0.379 96 Bl " 7 1 1.01E-06 >1.00E-04 >1.00£-04 MALME-3M MI. 0.348 1.102 1.114 1.135 0.931 0.382 0.171 102 104 77 • -51 2.37£-06 1. 20E-05 9.59£-05 HI ~-HEL 0.302 1. 275 1. 239 1.191 1.058 0.597 0.329 96 O! 76 30 3 3.84£-06 >1.00£-04 >1.00£-04 SK-MEL-2 0.519 1.3&7 1. 288 1.287 1. 051 0.578 0,637 69 " 61 7 14 1.61E-06 >1.00E-04 >1.00£-04 SK··ME:L-26 0.333 0.950 1.011 0.860 0.764 0.490 0.284 110 a5 70 25 -15 2.80£-06 4.28E-05 >1.00E-04 SK-IoiEL-S 0.390 1. 880 1.717 1.729 1. 495 0.111 0.179 " 90 " 22 -54 2.88£.-06 1.93E-05 8.66£-05 UACC-257 0.839 2.003 1.970 1. 934 1. BOg 1.093 0.850 07 " 83 22 1 3.48E-06 >l.OOE~04 >1.00£-04 DACe-62 0.522 1.400 1.334 1. 355 1.112 O.tilO 0.396 93 95 67 12 -2' 2.06E-06 2.ISE-OS >1.00£-04
OVarian Cancer IGROVI 0.506 1. .. 54 1.460 1. 446 1.304 0.805 0.559 lOJ ., 64 31 6 4.45£-06 >1.00E-04 >1.00£-04 OVCAR-3 D.770 1.499 1.440 1.349 0.860 0.823 0.679 92 79 12 7 -12 2.7SE-07 2.40£-05 >1.00E-04 OVCAfl-4 0.282 0.672 0.635 0.667 0.628 0.514 0.314 90 ., " '9 • 1.53£-05 >1.00£-04 >1.00E-04 OVCAf<-5 0.505 0.956 0.946 0.992 0.936 0.796 0.669 96 106 " " 41 4.11E-05 >1.00£-04 >1. 00E-04 rNCAF<-6 0.344 1.298 1.276 1.251 1. 096 0.514 0.471 " " 7' 16 13 2.98£-06 >1.00E-04 >1.00£-04 sK-aV-3
Renal Cancer 766-0 0.076 0.258 0.258 0.216 0.100 0.108 U98 ACHN 0.505 1. 650 1.661 1.623 1.163 0.602 0.570 101 " " 6 6 1.42E-06 >1.00E-04 >1.00£-04 CAKT-l RXr-351) 0.636 1. 030 1. 025 1.046 0.962 0.604 0.657 ,. 104 " .2 , 6.79E-06 >1.00£-04 >1.00£-04 RXF'-631 SN12C 0.611 1. 416 1.427 1.378 1. 216 0.851 0.496 101 95 75 30 -19 3.56£-06 4.10£-05 >1.00£-04 TK-·IO 0.662 1. 2 39 1.255 1.260 1.164 0.993 0.844 lOJ 104 67 '7 32 1.94E-OS >1.00E-04 >1.00E-04 UO-31 0.955 1. 696 1.662 1.670 1.494 1. 070 0.915 " " 73 15 -. 2.48£-06 6.10E-05 >1.00E-04
254 The synthesized compounds have been screened for
their antibacterial, anti-I/IV and anticancer activities.
The study also includes the evaluation of antitubercular
activity of the synthesized cOIIII'_ ",,1<;. The results are
compared with standard drugs.
The antibacterial study of the compounds 15
performed against E. coli, S. aureus and Salmonella typhi
Para A and anti tuber against
mycobacterium tuberculosis.
Table -1
Nineteen compounds have been tested of which few have
shown good activity. Compounds with A", ~ 3-0CI/3-C61/4 and
2-CI-C6H4 show maximum activ;1 .,;ainst E.c!oli while
compound No.4 of Table-l wi th Ar
maximum activity against ~ au reus & comnnllno No.2 shows
appreciable activity against Salmonella typhi Para A
These compounds exhibit notable antitubercular
activity at a concentration (5 fog/ml) which is lower
than all clinically used antituberculostatic drugs
except isoniazid .. As many as five compounds show this
remarkable activity.
Table - Z
These compounds do not show noteworthy anti-IIIV
activity. Compounds No.lU and II show more than 30%
act i v i ty. Both these compounds have chlor ine
substituent in phenyl ring at position I of oxadiazole
ring.
These compollnds show promising
against a number of cancerous cell
completely destroys four di fferent
anticancer activity
lines. Compound No. 14
types of cancerous
cells at comparatively lower concentration. Compound
No,IZ also inhibit cancerous cells of four different
types. These two different compounds have different aryl
groups therefore no structure-activity relation can be
established.
Table - 3
These compounds exhibit moderate antibacterial
activity against all the three bacteria 1 species.
Compounds No .10 CAr
(Cl)Z-C6H3 ) show high activity against E. Coli and
Salmonella ~~~ Para A.
ZSS
•
Zs6
Out of nineteen compollncls) fi Fteen have been
subjected to anti-tubercular activi ty. Compounds No.8,
11 and 13 show activity at lower concentration (30
ftg/ mI1 .
Table - 4
Twelve compounds of this series have been tested
against HIV. The screening results are not encouraging.
The anticancer activity results of tllese compounds
are excellent. Compound No.2 ('\r
completely inhihits the growth of as many as six
varieties of cancerous cells. Compound No.3 (Ar 3-NO Z-
C611 4 )also has noteworthy anticancer activity. Again,
compound No.6 (Ar = 3-CH 3-C 6H4 ) shows promise as it is
fully active against as many as six types of maliganancy •
Compounds No.5 (Ar = 2-CH 3-C6H4 ) and No.7 (Ar = 4-CII 3 -
C6H4 ) are also potent anticancer agents. Also compounds
with chloro suhstituent in ,\r group (No.10, 12 & 13)
show encouraging results.
It can be observed that introduction of CI/ 3 gr. ano
chlorine atom in Ar group Increases the activity.
However, introduction of second chlorine atom In Ar
reduces activity.
2S 1
Table - 5
In terms of antibacterial activity these compounds
are moderately active. Compounds No.9 and 12 show
comparable activity against Salmonella typhi Para A.
Compound No.14 with Ar = 3-0CH 3 -C 6 HS
shows exceptionally
high activity against ~ aureus with zone of inhibition of
higher than that of standard drug chloramphenicol. These
compounds show moderate activity against E. Coli.
Out of ninteen compounds six are ac t i ve
tuberculostatics at both the concentrations. Seven
compounds are active at lower and eleven at higher
concentrations.
Compound with Ar ; 3-0CI13
-C6
H4
shows good activity
against §..:. au reus and Salmonella !2:'r.!!.i. Para A species
and antitubercular activity at lower as well as higher
concentration. Compounds having Ar ; 2-0CH3
-C6
H4
and 4-
OC1I3
-C6
li4
show moderately good activity therefore it can
he concluded that introductioll or -1)C"3 )(r. is
advantageous.
Table - 6
As i t is observed III two previous series of
compounds these compounds also exhibit poor anti-IlIV
activity.
258
Thirteen compounds have been tested for their
Hnticancer activity. Four Ollt of these compounds exhibit
promising results. Compound No.4 and 8 show nearly 100%
activity against seven cancer cell lines.
As we conclude this section, the compound of this
serIes with Ar = 3-0Cfl3
-C6
1l4
catches our attention being
potent antibacterial and anti cancer agent.
The overall results of this part can be concluded
as under
These compounds have excellent anticancer activity.
Therefore it seems that basically this type of structure
should be studied in detail to trace out a practical
anticancer agent. As many as five compounds of Table-5
show anti tubercular activi ty at 5. QUi,/ml which is really
promiSing when compared with standard drugs. However,
with exception of some isolated L'ases (e.g. compound
No.l4 of Table-5) these compounds are only moderately
antihacterial and anti-IJIV agents.
Table - 7
These compounds show moderate ant i bacterial
activity. Only one compound (AI' = CoilS) show noteworthy
activity against S. aurells and Salmonella tyr hi Para A.
Z59
lIowever, three compounds (No.8, 9 and 10) show
comparable activity against E. coli. Remaining compounds ---
do not yield good results.
As many as seven compounds at higher (100 j4g/ml ) as
well as lower concent ra tion (3D ,Li,g/ml) whi Ie fourteen
only at higher concentrat ion (100 )L<g/ml) show
antitubercular activity.
Table - 8
These compounds show poor ant I IIIV activity with
compound No.4 (Ar =-4-CI-C6
H4
) showing maximum activity
(ZO.IZ%).
In case of anticancer activity compound no.4 shows
activity against as many as SiX cell lines with maximum
100% inhibition against one cell line. Compound No.9 (Ar
= - 3-NO Z-C 6H4 ) also exhibi ts promising activity.
Remaining compounds do not show noteworthy anticancer
activity.
Table - 9
These compounds show only moderate antibacterial
activity with compound No.IO (Ar
noteworthy act ivity agaillst E. col i
260
At lower concentration only three compounds show
ant i tubercul ar acti vi ty but at higher concentrat ion as
many as thirteen coml,ounds are fOJIIld active.
Table - 10
As in the case of ant i -IITV act i vi ty these compounds
do not have encouraging anti-IIIV activity.
Compound No.7 (Ar : -4-0H-C6
114
) shows powerful
anticancer activi ty against as many as six malignant
cell lines.
These compounds even having a salicylic acid
and j3-lactam moity do not possess promissing activity
in the above mentioned screening.
Table - 11
J3-lactams of this section having pyrimidine
lIuclellS show lTloderntu to gocld ;llllih.lt"rerial IIctivity. A
single compollnd is not effective against all the three
species. Compound No.2 (Ar : 2-01l-C6
H4
) shows activity
against Salmonella typhi Para 1\ which is comparable with
that of standard drJlg chloramphenicol. Compounds No.4
and R SIIOW appreciable activity against S. aureus and E.
coli respectively.
261
Table - 12
These compounds do not exhibit encouraging anti-fllV
activity as the highest activity ollserved is 16.14%.
These f3-lactam derivatives possess powerful
anticancer activity as they inhibit growth of large
number of cancerous cell s. Compounds No.2 (Ar
(Ar ; 4-NO -C6iI
4]-I.,No.6 (Ar
2
4 -OH-
fully active, however, at higher conc. As it can be seen
other compounds of this series also exhibit moderate
activity. One compound (No.1, Ar; 2-0H C6
H4
) has been
subjected to repeated testing being active at lower
concentration.
Table - 13
The (~)- oC-amino nitriles described in this table
show good to moderate antibacterial activity. Compound
No.14 shows excellent actiity against S. aureus with
zone of ibhibition (30 mm] being larger than that of
chloramphenicol (27 mOl). This compound shows moderate
activity against S. typhi Para A. These compounds do not
show very good activity against E. coli.
These compounds show moderately good antitubercular
activity as S I X of them are active at lower
concentration ( 30 .JLlg/ml) & twelve at higher
concentration (100 ),L{g/ml]. So far as antibacterial
activity is concerned compound No.14 shOUld be specially
262
mentioned having activity against ~ aur~~ Salmonella
!.~ Para A & mycobacterium tuberculosis !.!37~~
Table - 14
These ~-amino nitriles do not show potential
activity against IIlV as maximum activity observed is
only 16.57%. These cyano compOllnds show moderate
anticancer activity with the highest growth retardation
-4 of 96% at the lxIO M. concentration.
Table - 15
These (±)~ ~-amino nitriles even having salicylic
acid moiety have only moderate antibacterial activity.
Except compound No" 1 (Ar = C6"S) no other compound shows
appreciable activity against S. aureus and Salmonella
typhi Para A. However, as many as three compounds
(No.8, 9 and Ill) show good activity against E. coli.
These compounds show good antituhercular activity
as seven compo'lI1ds are active at lower as well as higher
concentration while six are active only at higher
concentration.
Table - 16
Tbe anti-IIIV
from 10.82% to
activity of
16.66% which
these
is
compounds ranges
not
Similarly. anti-cancer activity results
promising.
are also
moderately good with maximum growth retardation observed
in case of compound No.7 (Ar • 2-01-1-C IO " 6 )'
Table - 17
These (!) - ~ -amino nitriJes having pyrimidine
nucleus do not give promissing antibacterial activi ty.
Only one compound (No.10)possess~ good activity against
E. coli.
In terms of antitubercular activity three compounds
are active at both the concentrations while nine are
active at higher concentration only.
Table - 18
The anti-IIlV act i vi ty of the compounds has slightly
good results with two compounds having )24 % activity.
263
Dul of 7 COlliPOllllds (lilly one 1111 S Ilottlwortlly
allticancer activity (Ar a 2-(lll-I-Clll
IJ 6 ).
We have studied and reported biological activity of
oxadiazoles, p-lactams and (:l oC-amino nitri les.
As it can be seen from the data, few compounds show
activity higher than that of the standard drugs or
comparable wi th it. However, i t is observed that
incorporation of salicylic acid moiety either in
j3-lactams or (=.l v{-amino nitriles does not increase
antibacterial activity.
Some of the oxadiazoles reported in this thesis
exhihit antitubercular activity at a concentration which
is less than that of many other cl inically used drugs.
Unfortunately, because of some difficulties, 'in vivo'
testing of these compounds did not materialize. It is
expected that researchers will definitely find these
compounds interesting for further study in the search of
new potential antituberculostatics.
The anticancer activity results of oxadiazoles
indicate that with different substituents, activity is
retained therefore it can be inferred that oxadiazole
nucleus with suitahle suhstituents must be associated
with anticancer activity. Therefore this nucJeus must be
264
265
explored for finding out new IDtmliill anticancer agents.
Pyrimidine derivatives (e.g. 5-fluoro uracil) are
clinically used as anticancer agents. Some activity must
be associated with the pyrimidine moiety as most of the
compounds of Table-12 show promising anticancer
activity. However, (.:':.)
much
oC-amino nitriles containing this
effective. Therefore it can· be moiety are not
concluded that combination of ,B-Iactam and pyrimidine
structures can yield highly potential anticancer agents.
Therefore from our study we have come to a conclusion
that these compounds should be structurally modified to
find out new chemotherapeutics In the treatment of
cancer.
Sccti on II
Spectroscopic Analysis
266
DISCUSSION:
We have confi rmed the structures of synthesised compounds by
their infrared (IR) spectra and proton magnetic resonance (PMR)
spectra.
IR Spectra.
The IR spectra have been recorded on Carl Zeiss IR on KBr
pellets at C.S. & M.C.R.I., Bhavnagar in the range of 2.5 to
16.5 p-I.. (4000 - 600 cni-1 ). The data have been interpreted and
discussed.
PMR Spectra.
The PMR spect ra have been recorded on Jeol 100 MHz FT NMR at
C.S. & M.C.R.I., Bhavnagar using appropriate deuterated solvents
(Acetone - D6
, DMSO-D6
, CDCl3
, etc.).
1. The IR Spectra of 2-(N-phenyl carboxamido methyl thio) -5-ben-
zyl - 1,3,4 oxadiazole, showed following characteristic
bands at :
3290 cm- 1 ( -NH str., acetamido group), 1720 cm- 1 ( >C~O str.,
acyclic), 1650 cm- 1 (-CO-NH-linkage), 1600 -1 cm
C-O-C str., cyclic), 1430
)C~N-str. ,
-1 cm ( -CH 2 ' cyclic), 1520 cm-1
benzylic), 1410 cm-1 (S-CH 2 str., methylene str., strong
band), 1280 cm- 1 (~N-N~C<str., cyclic str.,) 690 and 740 cm1
(C-H bending for mono substituted benzene ring).
PMR spectrum of the compound showed signals as follows
9.6 2i (broad signal due to -NH proton) , 6.8 7.2 6
(multiplet, aromatic protons), 2.8'b (S-CH2
-singlet.), 2.3 .;
( -CH 2 5 i ng 1 e t ) .
267
(Z) The IR spectra of
thio}-5-[4-(4-chloro
Z-(N -I'helyl
benzylidine}
carboxamido
amino
methyl
phenylJ-
1,3,4-oxadiazole showed following characteristic bands:
3310 cm- 1 (-NH str., acetamido group), 1725 cm -1 ( " c=o /
str., acyclic), 1650 cm-1 (-CO-Nil linkage), 1600 cm-1 (jC=N
str. cyclic), 1520 cm-1 (C-O-C str. cyclic), 1400 cm-1 (S-CH2
str.), 1280 cm-1 (=N-N=C str., cyclic str.), 820 cm- 1 (C-H
bending for 1,4-disubstituted benzene ring), 690 cm-1 (C-H
bending, mono substituted benzene ring), 770 cm-1{C-Cl str.
for benzene substitution}.
PMR spectrum of the compound showed signals as follows:
9.5 ~ (broad signal due to -NH proton), 6.8-7.3 ~ (multiplet
aromatic protons), 1.94 b (singlet, Ar-CH-str.), 2.9 0 (-CH 2
singlet) .
(3) The IR spectra of 2 (N-phenyl carboxamido methyl
thio)-5-(4-acetyl amino phenyl )-1,3,4-oxadiazole following
characteristic bends at :
3275 cm-1 (-N-H str., acetamido group), 1720 cm-1 ()C=O str.
acyc lic ketone), 1650 cm -1 (-CO-NH 1 i nkage), 1600 cm- 1 (:; C=N
str., cyclic), 1520 cm-1(C-0-C str., cyclic), 1400 cm-1 (S-CH2
str.), 1360 cm-1 (-C-H-bending-CO-CH group), 1280 cm-1 (=N-N=C
str. cyclic), 840 cm-1 (C-H bending 1,4-disubstituted benzene
ring}, 690 cm-1 (C-H bending, monosubstituted benzene ring}.
PMR spectra of the compound showed following signals:
9.3); (broad signal due to -NH proton), 6.8-7.46 (multiplet,
aromatic protons), 2.9g (-CH 2singlet).
268
(4) The IR spectra of 1-phenyl-3-chloro-4-(indol-3-yl)-2-oxo
azetidine showed characteristic bands at
3240 cm-1 (-N-H str.), 3050 & 2900 cm-1 (-C-H str.,
aromatic), 1740 cnr1 ()C=O str., strong band, -lactam
ring), 1550 cm- 1 (-N-H bending for heterocyclic ring), 1310
cm-1 (-C-N str., heterocyclic ring), 780 cm-1 (C-Cl str.,
~lactam ring),690 & 740 cm-1 (-C-H bending, mono substituted
benzene ring).
PMR spectra of the compound showed following signals:
8.488 (-N-H proton of indole ring), 7.68 6 (aromatic
protons), 4.58 b (-CO-CH-Cl of j3-lactam ring), 4.82S (-N-CH
signal).
(5) The IR spectra of 1-(2-hydroxy benzoyl amino)
-4-phenyl-3-chloro-2-oxo azetidine showed characteristic
bands at
3350 cm -1 (-OH st r. , phenolic-OH), 3270 -1 cm (-N-H s t r. ,
acyclic-CO-NH-) ,3020 cm-1 (-C-H str., aromatic ring), 1740 cm-1
(?C=O s t r. , strong band, f3-lactam ring) 1640 cm C=Ostr.,
strong band, acyclic ketone) , 760 cm -1 (-C-H bending,
1,2-disubstited benzene, ri ng ) , 740 cm-1 (C-Cl bending,
-lactam ri ng) , 700 and 740 cm -1 (C- Cl bending, mono
substituted phenyl ring).
PMR spectra of the compound showed following signals:
9.2 b (-OH, aromatic), 7.80S (-CO-NH, acyclic), 5.6 & (-N-CH
signals), 4.2 ~ (-CH-CO-Cl. J3-lactam ring), 4.86 (-C-NH
aromatic proton), 7.2-7.4 (multiplet, aromatic protons).
269
(6) The IR spectra of 1-(4-hydroxy-methyl pyrimidin-1-yl
amino)-4- 4-methoxy phenyl)-3-chloro-2-oxo azetidine
showed following characteristic bends at :
3640 cm- 1 (-OH group, phenolic), 3270 cm- 1 (-N-H str.,
acyclic), 2960 & 1565 cm- 1 (-C-H & C-C str;, deformation
vibration of pyrimidin heterocycle), 1740 cm-1 ~C-O,
strong band, -lactam ri ng ) , 1620 cm-1 (:C-N-str. ,
heterocyclic ring), 1250 cm- 1 (-C-O-C str., aromatic
ether) , 840 em -1 ( -C-H bendi ng, 1,4-disubstituted
benzene), 760 em -1 (-C-Cl st r. ,,B-lactam).
PMR spectra of the compound showed following signals:
10.2 b(-OH proton, singlet), 7.4-7.6,l;(multplete aromatic
ring), 5.7,s(proton in the pyrimidin ring), 5.4~(-NH
proton, Ar-NH str.), 4.2b(-CO-CH-Cl,j3-1actam ring), 3.86
(-OCH.3 str.), 2.16 f-CH3 ' pyrimidine ring).
(7) The IR spectra of -(phenyl acetyl hydrazino)-2-hydroxy
phenyl acetonitrile) showed following characteristic
bands at:
3350 cm-1 (-OH str., phenolic-OH), 3220 cm- 1 (-NH str.,
acetamido group), 2250 cm-1 (-C:N str., nitrile group),
1690 cm-1 (lC-O str. acyclic), 1650 cm- 1 (-CO-NH linkage),
1510 em -1 (:C-C~str., aromatic ring), 1395 cm- 1 (-CH 2 str.
methylene), 1320 em -1 (-C-N-str. -NH-CH bending), 850 cm- 1
(C-H bendi ng for 1, 4-di subs t ituted benzene ri ng), 690
and 740 em -1 (-C-H bending for mono subs ti tut ed benzene
ring) .
PMR spectrum of the compound showed following signals:
9.66(sharp broad signal due to -NH protons), 6.8-7.2 ~
(multiplet aromatic protons), 4.2 (-CO-NH linkage), 2.3 h
270
(-CH 2singlet).
(8) The IR spectra of -(2-hydroxy benzoyl hydrazino)-2-chloro
phenyl acetonitrile showed following characteristic bands
at:
3330 cm-1 (-OH str., phenolic-OH), 3250 cm-1 (-NH str.,
acetamido group), 2254 cm- 1 (-C':N str. nitrile group),
1690 cm- 1 (C=O str., acyclic), 1520 cm- 1 ()C=C<.str.,
aromatic ring), 1320 cm-1 (-C-N-str.,-NH-CH bending), 860
cm- 1 (C-H bending for 1,4-disubstituted benzene ring),
780 cm-1 (C-CI str.).
PMR spectrum of the compound showed following signals at:
9.6,s(signal due to -NH protons), 7.95b(-OH phenolic),
6.8-7.1 S (multiplet
li nkage) .
aromatic protons), 4.2b(-CO-NH
(9) The IR spectra of -(4-hydroxy-6-methyl pyrimidin-2-yl
hydrazino)-4-methoxy phenyl acetonitrile showed following
bands at:
3380 cm- 1 (-OH str. phenolic-OH), 3320 cm-1 (-NH str.,
acetamido group), 2250 cm- 1 (-C;;N str., nitrile group),
1670 cm-1 (-C=N-str. pyrimidine str.), 1510 cm- 1 (iC=C<
str., aromatic ring), 1350 cm- 1 (-CH-NH-str.), 1250 cm- 1
(C-O-C linkage, due to Ar-OCH ), 1330 cm 1 (C-H bending,
methyl group), 830 cm-1 (C-H bending 1.4-disubstituted
benzene ri ng) .
PMR spectrum of the compound showed following signals at:
9.6S(sharp signals due to -NH protons), 7.5S(-OH,
phenolic), 6.9-7.2b(multiplet aromatic protons) 2.5~(-OCH3)
2.05~(Ar-CH3 ~.
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